Takotsubo Cardiomyopathy: Current Perspectives on Pathophysiology, Diagnosis, Technology, and Management

1. Introduction

“And I will give you a new heart, and a new spirit I will put within in you.

And I will remove the heart of stone from your flesh,

And give you a heart of flesh.”

(Holy Bible, English Standard Version, Ezekiel 36:26)

Takotsubo cardiomyopathy (TCM), also known as stress induced cardiomyopathy or “broken heart syndrome”, is an acute, reversible cardiomyopathy that most commonly affects postmenopausal women [1,2,3], with mortality more than double in men [4], and is typically precipitated by intense emotional or physical stress [5]. First described in Japan in case reports in the early 1990s [6,7] and then later in a multicenter study [5], the syndrome derives its name from the resemblance of the left ventricular silhouette to a “takotsubo”, a traditional Japanese octopus (tako-) pot (-tsubo) trap with a narrow neck and round base. Although its clinical features often mimic those of ST-elevation myocardial infarction (STEMI) [1], coronary angiography in TCM often reveals no significant coronary obstruction. However, co-existing coronary artery disease may still be present in some patients. In this review, we provide an update on the pathophysiology, diagnosis, and management of TCM.

2. Pathophysiology

Catecholamine surge, inducing regional wall remodeling and motion abnormalities, is a central hypothesis in TCM pathogenesis. Triggered by acute stress, patients with TCM exhibit a rapid surge of plasma catecholamines, epinephrine, norepinephrine, and dopamine, with levels reported to be two to three fold higher than those with myocardial infarction [8] and up to 34 times normal values [9]. Rodent models of TCM have successfully replicated its key features using synthetic sympathomimetics [10,11,12], and case reports of TCM associated with pheochromocytoma further support the role of excess catecholamines in its pathogenesis [13,14,15,16]. Moreover, TCM patients receiving catecholamine therapy have been reported to have increased short- and long-term mortality [17,18]. Excess catecholamines are thought to exert direct toxic effects on cardiomyocytes [19,20,21] through alterations in calcium handling [22,23,24,25], disruption in mitochondrial functioning [26,27], and an increase in oxidative stress [28]. Likely due to its higher relative proportion of β-adrenergic receptors relative to the basal segments, the apex of the left ventricle is more susceptible to catecholamine-induced dysfunction [29,30]. This heterogeneous receptor distribution explains the characteristic apical ballooning seen in the majority of TCM cases.

Emerging evidence suggests that the transient myocardial dysfunction characteristic of TCM may also be driven by complex neurocardiac interactions [31]. Multimodal neuroimaging across different phases of TCM, including fMRI, PET, structural MRI, and diffusion tensor imaging, has revealed a dynamic and temporally evolving pattern of brain abnormalities. In the acute phase (within days of diagnosis), patients exhibit markedly increased amygdala metabolic activity, which significantly subsides within one month, consistent with acute hyperactivation of limbic stress-regulatory circuits [32]. Concurrently, acute structural and functional changes include reduced limbic volumes, particularly within the hippocampus, alongside increased cortical thickness in regions such as the insula and thalamus. These alterations are accompanied by enhanced structural connectivity and a mixed pattern of hyper- and hypoconnectivity in networks governing emotion and autonomic regulation [33]. In the chronic phase, the brain-heart axis appears to undergo further remodeling. One study examining patients approximately one-year post-event reported widespread reductions in resting-state functional connectivity across sympathetic, parasympathetic, and default mode networks, suggesting persistent network disruption [34]. In contrast, a separate study conducted nearly three years post-event found increased resting-state and stress-induced functional connectivity in core limbic and central autonomic structures, including the hippocampus, insula, and anterior cingulate cortex [35]. Though seemingly contradictory, these findings likely reflect a time-dependent trajectory—from early disintegration of regulatory networks to later-stage compensatory or maladaptive hyperconnectivity—underscoring the evolving and dynamic nature of brain-heart dysregulation in TCM.

TCM represents a striking convergence of emotional stress, neurohormonal activation, and myocardial vulnerability. The hallmark transient ventricular dysfunction is thought to result from a surge in catecholamines, modulated by regional variability in adrenergic receptor density. However, growing evidence suggests that persistent alterations in central neural circuits, particularly those involved in stress regulation and autonomic control, may extend beyond the acute cardiac event. Continued investigation into the brain–heart axis holds promise not only for elucidating individual susceptibility but also for informing targeted neurocardiac, and potentially psychiatric, interventions aimed at prevention and recovery.

3. Clinical Presentation

TCM typically presents with acute chest pain, dyspnea, syncope, or dizziness, with chest pain being the most common symptom (>75%), often making it clinically indistinguishable from acute coronary syndrome (ACS) [1,36]. Patients may have a history of recent emotional or physical stressors, which are commonly negative, such as grief, conflict, or illness, however in some cases TCM can also be triggered by intense positive experiences. As such, a detailed history may assist with diagnosis. Serious complications include ventricular arrhythmias (such as ventricular tachycardia and ventricular fibrillation), bradyarrhythmia’s, sudden cardiac arrest, significant mitral regurgitation, and ventricular free wall rupture [37]. Patients may also co-present with overlapping features of both ACS and TCM, and in some cases, an ACS event itself can act as a physical stressor that triggers TCM [37,38]. Coronary angiography may reveal a culprit lesion, but the degree and pattern of wall motion abnormalities often appear disproportionate to the severity of coronary disease or the distribution of epicardial coronary involvement [36,39]. Another important differential diagnosis is myocarditis which can present with acute chest pain and heart failure symptoms, typically showing global systolic dysfunction with occasional regional involvement.

4. Assessment, Technology, and Diagnosis

Given the overlap in clinical presentation among TCM, ACS, and heart failure, physical examination findings can also appear similar. Common findings include respiratory distress, rales on auscultation, hypotension, tachycardia, cool extremities, and murmurs due to left ventricular outflow tract obstruction (LVOTO) or acute mitral regurgitation [40]. The differential diagnosis of acute chest pain is broad and includes both cardiovascular and non-cardiovascular causes. Cardiovascular etiologies include myocardial infarction with non-obstructive coronary arteries (MINOCA) and acute aortic syndromes. Non-cardiac causes include pulmonary embolism, pneumothorax, and esophageal rupture. In cases of MINOCA, the underlying mechanisms are typically coronary vasospasm, microvascular dysfunction, or spontaneous coronary artery dissection.

Diagnosing TCM can be challenging as it closely mimics ACS on ECG and biomarker testing [1]. Troponin is elevated in about 87% of TCM cases, though typically to a lesser degree than in ACS, while BNP levels are elevated in over 82%, often more significantly [1,40,41]. Many TCM patients also have incidental, non-obstructive coronary artery disease (CAD), which may not be related to the acute event [36,39]. In stable patients with low suspicion of ACS or suspected recurrent TCM, coronary CT angiography can serve as a valuable non-invasive diagnostic tool. Its role in this setting is to evaluate the epicardial coronary arteries and effectively rule out high-grade stenosis, obstructive CAD, pulmonary embolism, or acute aortic syndromes [39,40,42]. However, the overlap in presentation between TCM and ACS can lead to underdiagnosis of ACS in patients presumed to have TCM. Studies suggest that patients with TCM who do not undergo angiography may have higher mortality rates compared to those who do, highlighting the importance of a thorough diagnostic approach (Figure 1) [43,44].

For patients with TCM, as with anyone presenting with chest pain, ECG is a crucial component of the initial diagnostic evaluation. Common ECG findings in TCM include ST-segment elevation, T-wave inversion, and QT interval prolongation, the latter of which may increase the risk of malignant arrhythmias such as torsade’s de pointes, discussed further in the arrhythmia section of TCM complications [40]. Although ECG abnormalities are frequently present, their sensitivity for diagnosis remains limited [45]. While several studies have proposed ECG criteria to differentiate TCM from ACS, data remains insufficient due to small sample sizes and heterogenous study designs [45]. However, certain features can aid in differentiation. For example, ST-segment depression, commonly observed in ACS, occurs significantly less often in TCM, a distinction incorporated into the InterTAK Diagnostic Score [45]. This scoring system combines clinical variables, such as emotional or physical triggers and neurologic disorders, with ECG findings to improve diagnostic accuracy and help distinguish TCM from ACS [40,46]. While no single ECG characteristic definitively identifies TCM, the overall pattern of ECG changes alongside clinical context provides valuable clues in diagnosis.

Cardiac imaging is essential for the diagnosis of TCM. Ventriculography provides a definitive diagnosis by confirming the characteristic wall motion abnormalities and associated myocardial edema. [39]. Importantly, the absence of late gadolinium enhancement (LGE) on cMRI helps distinguish TCM from ACS and myocarditis [39,40,42,47,48]. Cardiac MRI is also valuable in identifying complications such as left ventricular thrombus or right ventricular involvement, which have prognostic implications [39,42,48]. Echocardiography provides visualization of left ventricular shape, allowing the identification of classic apical dysfunction as well as TCM variants (Figure 2). It also plays a critical role in detecting severe complications: including LVOTO/ejection fraction, valvular dysfunction, right ventricular involvement, thrombus formation, and ventricular wall rupture.

Nuclear imaging has not yet been validated for diagnosing TCM, but it is increasingly used to evaluate perfusion defects and assess wall motion abnormalities. While the role of microvascular dysfunction in TCM remains unclear, it has been proposed as a potential contributor to the syndrome’s pathophysiology. In this context, nuclear techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) show promise, though their use remains largely limited to research settings [49]. The clinical utility of perfusion assessment in TCM is still debated, as studies have reported increased perfusion while others have shown decreased perfusion. [50,51]. Notably, some investigations in patients with TCM have observed increased tracer uptake in basal myocardial segments, possibly reflecting heightened metabolic demand or compensatory remodeling in response to apical dysfunction [50,52]. There have been varying results with regards to both increased and normal perfusion of the left ventricle that are akinetic in patients with TCM. It is unclear whether these differences in perfusion reflect a continuum of impaired perfusion to quick recovery, distinct phenotypes of the same disease, or possibly other conditions manifesting as TCM [52]. Looking ahead, microvascular evaluation using nuclear imaging could provide valuable prognostic insights in the acute phase of TCM, potentially helping predict ejection fraction, the number of akinetic segments on echocardiography, and the extent of perfusion defects [53].

TCM can be difficult to distinguish from ACS at initial presentation, so patients should be promptly transferred to a cardiology facility with imaging capabilities and a cardiac catheterization lab [40]. Initial management typically follows ACS protocols, including aspirin, a P2Y12 inhibitor, and heparin, with intensive care required for those in cardiogenic shock or post-cardiac arrest [40]. Continuous ECG monitoring is essential, as prolonged QT intervals can lead to torsades de pointes, or the development of AV block. Management is complicated by the lack of high-quality randomized controlled trials in TCM. Retrospective data suggest that angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) may improve one-year survival, while beta-blockers have not consistently shown a survival benefit [40,54]. Although some observational studies suggest potential long-term benefit from beta-blockers, particularly in reducing mortality, their effect on recurrence remains unclear, and the observational nature of these studies limits generalizability [54,55].

Treatment of heart failure in TCM depends on congestion and hemodynamics. It’s crucial to assess for LVOTO via transthoracic echocardiography [39,56]. For patients with pulmonary congestion, indicated by dyspnea, orthopnea, and crackles, diuretics are helpful to reduce congestion. In hemodynamically stable patients, beta blockers can be used to manage hypertension and may be especially helpful in LVOTO by reducing hypercontractility and relieving obstruction [57,58].

5. Complications

The most common complication of TCM is acute heart failure (Table 1) [40]. Cardiogenic shock is often associated with LVOTO, acute mitral regurgitation, or right ventricular involvement, each of which can contribute to hemodynamic instability. Arrhythmias, including ventricular arrhythmias, asystole, and bradyarrhythmias, are also frequently reported. Patients with an apical ballooning pattern are at risk for developing a left ventricular thrombus. Notably, the combination of apical ballooning and elevated troponin levels confers a significantly higher risk than apical ballooning alone [59]. In rare cases, ventricular free wall rupture may occur, which can be fatal if not promptly recognized and managed [37,60].

5.1. Acute Heart Failure/Cardiogenic Shock

Systolic heart failure is the most common acute complication of TCM, with risk factors including advanced age, reduced left ventricular ejection fraction (LVEF), and elevated troponin levels [61]. Severe cases may require supportive interventions like mechanical ventilation, inotropes, or an intra-aortic balloon pump (IABP), especially when complications such as pulmonary edema, mitral regurgitation, or LVOTO arise [37].

Management of cardiogenic shock in TCM is largely determined by the presence of LVOTO [56]. While inotropes are often used to increase cardiac output, they can worsen LVOTO by enhancing contractility, which paradoxically exacerbates the shock [57,58]. In such cases, vasopressors like phenylephrine may be preferred to support blood pressure. Rate-controlling agents, such as beta-blockers, help improve ventricular filling time and reduce obstruction [57,58]. Serial echocardiograms are crucial for monitoring LVOTO progression, and if patients fail to respond to medical therapy, advanced interventions like IABP, Impella, or Extracorporeal Membrane Oxygenation (ECMO) should be considered to manage refractory shock.

5.2. Hemodynamic Complications

• Left ventricular outflow tract obstruction (LVOTO)

In the acute phase of TCM, a dynamic LVOTO can develop due to basal hypercontractility and apical stunning, often leading to systolic anterior motion of the mitral valve and resultant mitral regurgitation. Tethering of the mitral valve due to acute left ventricular failure has been reported as a mechanism of mitral regurgitation in patients with TCM [62]. This complication occurs in approximately 10–25% of patients and significantly impairs left ventricular systolic function [61]. These cases are often the most challenging to manage, as both LVOTO and mitral regurgitation further compromise cardiac output. Diagnosis is typically confirmed with Doppler echocardiography. Inotropes and nitrates may worsen the obstruction, while beta-blockers can help reduce it [57,58].

• Valvular dysfunction

Acute mitral regurgitation affects patients with TCM and is associated with more severe outcomes, including reduced LVEF and an increased risk of heart failure or cardiogenic shock. Prevalence has been estimated at 19-25% with one study showing 21% [63]. This condition is commonly caused by systolic anterior motion of the mitral valve, often in conjunction with LVOTO, or by apical tethering of the mitral valve apparatus [62]. Mitral regurgitation typically improves as left ventricular function recovers.

• Right ventricular involvement

RV predominant TCM is a rare subtype characterized by acute RV failure and cardiogenic shock, with imaging showing RV wall motion abnormalities and preserved LV function [64]. It is reported in approximately 11–50% of cases. Management is primarily supportive and may require inotropes or mechanical ventilation. RV involvement has been associated with worse clinical outcomes, including heart failure, cardiac arrest, and prolonged hospitalization [65]. It is also linked to higher rates of intensive care unit admission and increased mortality [37,39,65,66].

• Thrombus formation

Thrombus formation in the akinetic ventricular apex occurs in approximately 1.3–8% of patients with TCM and can lead to serious complications such as stroke or systemic arterial embolism [1,61,67]. Thrombi most commonly develop between 2 and 5 days after symptom onset, typically during the period of persistent left ventricular dysfunction. However, thrombi may also form up to 14 days later, even after apparent recovery of LV function [59]. The role of prophylactic anticoagulation in high-risk TCM remains unclear but may be warranted in selected patients. A 3-month course of oral anticoagulation can be considered in individuals with apical ballooning and elevated troponin levels, as they are at increased risk for LV thrombus formation [59]. Although no randomized studies have compared vitamin K antagonists (VKAs), such as warfarin, to direct oral anticoagulants (DOACs) in this context, DOACs are generally preferred due to their ease of use. Recent guidelines support DOACs as a non-inferior alternative to VKAs in managing thromboembolic risk [68].

• Arrhythmias

The role of beta-blockers in treating TCM remains uncertain, particularly in patients presenting with arrhythmias. While acute arrhythmia management generally follows standard protocols, caution is advised with medications that prolong the QT interval, as over half of TCM patients present with QT prolongation [1,40]. Although TCM is often perceived as a benign condition, it carries significant proarrhythmic risk [69]. Malignant arrhythmias may include ventricular tachycardia, ventricular fibrillation, asystole, high-grade AV block, and sick sinus syndrome [69,70,71]. Life threatening arrhythmias constituted 4.2% of cases [70,72], with atrial fibrillation being the most commonly observed arrhythmia [37,70].

Implantable cardioverter-defibrillator (ICD) placement may be considered for patients with life-threatening arrhythmias; however, given the typically reversible nature of TCM-related ECG and ventricular dysfunction, long-term benefit remains unproven. As such, ICD and wearable cardioverter-defibrillator use should be evaluated on a case-by-case basis, guided by clinical judgment and patient-specific risk factors. Key considerations for ICD implantation include the presence of life-threatening arrhythmias at presentation, such as ventricular tachyarrhythmias or cardiac arrest, as well as persistent long-QT that increases risk of sudden cardiac death despite optimal medical therapy. Similarly, decisions regarding pacemaker placement are influenced by symptomatic bradyarrhythmia, high-grade AV block, or hemodynamic instability, which may necessitate temporary pacing support [70,71,72,73].

• Ventricular free wall rupture

Mechanical complications of TCM, though rare, can be severe and include ventricular free wall rupture or interventricular septal wall rupture. They typically occur in older females, many of whom have a history of hypertension. Some theories to explain this include postmenopausal hormonal changes and anatomical factors such as smaller left ventricular chamber sizes at baseline [60]. While the prognosis remains poor without prompt surgical treatment, timely intervention can significantly improve survival outcomes [74,75]. This complication emphasizes the importance of heightened clinical vigilance and prompt intervention in the management of TCM, particularly in patients presenting with severe manifestations.

6. Takotsubo Variants

• Apical

The apical variant of TCM (Figure 2) is the most common form, accounting for 81.7% of cases, followed by the midventricular type (14.6%). Basal and focal types occur less frequently, representing approximately 2.2% and 1.5% of cases, respectively [1]. Although rare, other variants such as global hypokinesia, biventricular dysfunction, and isolated RV involvement have been reported. These atypical presentations can be associated with severe hemodynamic instability and cardiogenic shock. As most existing literature focuses on the apical form, the less common variants of TCM warrant further discussion, especially given their unique clinical associations and implications for prognosis.

The apical variant is most frequently observed in TCM triggered by emotional stress, or primary TCM, where no clear precipitating factor is identified [76]. In contrast, midventricular and basal variants are more often associated with physical stressors, such as acute medical conditions, surgical procedures, or neurological events, and are therefore categorized as secondary TCM [76]. Of these, the midventricular form has been more commonly linked to surgery, while the basal variant is frequently observed in patients with neurological disorders. Patients with secondary TCM tend to experience longer hospital stays and a higher incidence of in-hospital complications, including more severe heart failure and a greater frequency of ventricular arrhythmias. Early mortality is also increased in cases triggered by secondary causes, whereas patients with primary TCM typically have a more favorable prognosis [76]. Notably, individuals with TCM secondary to neurological conditions have shown worse long-term survival, likely due to the additive effects of both TCM and the underlying neurological disorder [76].

• Midventricular

The midventricular ballooning pattern is characterized by reduced or absent contraction in the middle portion of the LV, while the apex and base of the LV retain normal function [77]. This pattern shares similarities with the well-known apical ballooning, particularly in its strong female predominance [77]. Midventricular ballooning is thought to be a variant of apical ballooning, and long-term follow-up has shown that patients generally experience no recurrence or significant long-term complications [77]. Like the apical variant, the management of mid-ventricular TCM necessitates careful evaluation for LVOTO and valvular abnormalities. This assessment is especially critical in hemodynamically unstable patients, as it plays a key role in guiding appropriate treatment strategies.

• Basal (reverse or inverted Takotsubo)

Patients with the basal variant of TCM, also referred to as the reverse or inverted variant, as it presents with basal hypocontractility and apical hypercontractility. This is the opposite pattern that is seen in the classic apical form, and these patients tend to be significantly younger than those with apical or midventricular variants [78]. Despite presenting with a lower initial LVEF, individuals with the basal variant tended to experience more rapid recovery [78]. The basal form has also been observed in patients with neurological injuries, including intracranial hemorrhage, multiple sclerosis, and serotonin syndrome [79]. Regional differences in catecholamine sensitivity are driven by higher β-adrenergic receptor density at the apex and greater sympathetic nerve density at the base [29,30]. This leads to predominant norepinephrine stimulation at the base and epinephrine effects at the apex during acute stress, which may help explain the development of basal versus apical TCM variants.

7. Prognosis

TCM has a mortality rate similar to acute myocardial infarction, with in-hospital mortality ranging from 2-5% [1,2,3,37]. Poor outcomes are associated with factors such as acute neurologic or psychiatric conditions, elevated troponin levels, age over 75, and admission LVEF <45% [61,80]. Men tend to experience worse clinical outcomes than women, with higher incidences of cardiogenic shock, ventricular arrhythmias, cardiac arrest, and respiratory failure requiring ventilation. In contrast, women are more likely to experience acute systolic heart failure [81].

The type of trigger appears to influence both the clinical presentation and prognosis of TCM, ranging from acute neurological events to surgical stressors, such as following kidney transplant [82]. Physical stressors are more commonly identified as triggers in men, whereas emotional stress is more frequently reported in women. Notably, neurologically triggered TCM is associated with the poorest outcomes, while emotionally induced cases tend to have a more favorable prognosis [76]. There are disparities in outcomes between men and women, which may be explained by the predominance of physical triggers in men, particularly severe neurological events, which are linked to more complicated clinical courses and higher mortality [83]. Interestingly, episodes of severe hypoxia have emerged as a particularly detrimental trigger, with associated worsened outcomes [84]. Perhaps this is related to the sympathetic responses to hypoxia which, through activation of peripheral chemoreceptors, may amplify the overall catecholaminergic drive. Furthermore, patients with secondary TCM exhibit higher mortality, increased rates of major adverse cardiovascular events and more frequent hospital readmissions [76,85]. These findings suggest that the underlying trigger in secondary TCM plays a significant role in the poor prognosis observed.

Although there are no formal guidelines regarding the timing of repeat echocardiography to assess LVEF, reassessment is commonly performed around 4 to 6 weeks post-discharge. Follow-up imaging showed normalization of LVEF by 60 days after admission [1]. Patients with a history of TCM have been found to have a twofold increased risk of hospitalization for any cause compared to the general population, with a particularly elevated risk for cardiovascular events such as acute myocardial infarction, heart failure, and arrhythmias. However, when compared to individuals recovering from acute myocardial infarction, those with TCM tend to experience lower rates of hospital readmission [86].

The recurrence rate of TCM has been estimated to range from 1.5% to 9.6% [87,88,89,90]. Currently, there are no randomized controlled trials evaluating the efficacy of pharmacologic therapies, such as beta-blockers or ACEi/ARBs, in preventing recurrence [54,55]. While some studies suggest that beta-blockers may reduce mortality, they have not demonstrated a significant effect on recurrence rates. The risk factors for recurrence remain poorly defined, and it is unclear whether recurrent episodes are associated with an increased risk of future cardiovascular events or mortality. Interestingly, up to one-third of patients present with a different variant of TCM during recurrence compared to their initial episode [87,88,91]. One theory suggests that regions affected in the initial event may develop a form of localized myocardial adaptation, making them less susceptible to involvement in future episodes. This may explain the variation in regional patterns seen in recurrent cases, although the underlying mechanisms remain unknown.

8. Limitations

Understanding and managing TCM is limited by the absence of randomized controlled trials, with most evidence based on retrospective and observational studies. The condition’s variable clinical presentation, including fewer common variants, and uncertain pathophysiology further complicate diagnosis and treatment. The diverse triggers of TCM, such as emotional, neurological, or physical stress, result in heterogenous patient populations, creating challenges in understanding the disease’s full spectrum and tailoring management to individual cases. Diagnosis is also challenging because TCM mimics other acute life-threatening conditions such as ACS or myocarditis, increasing the risk of misdiagnosis or delayed treatment. Additionally, long-term outcomes including the effectiveness of therapies such as beta-blockers remain unclear. This lack of high-quality data hinders the development of standardized treatment and follow-up strategies, highlighting the need for prospective research.

9. Conclusion

Management of TCM often mirrors that of ACS, given the similar clinical presentation and the necessity of excluding alternative diagnoses such as myocarditis [40]. Although no randomized controlled trials have established guideline-directed therapy for TCM, observational studies suggest a potential survival benefit with ACEi or ARBs, whereas beta-blockers have not demonstrated consistent efficacy [54,55,92]. Management should be individualized based on the patient’s acute presentation, with treatment guided by hemodynamic status, electrocardiographic findings, and the presence of pulmonary congestion, low-output states, or cardiogenic shock. Additionally, clinicians should consider thromboembolic risk and initiate prophylactic anticoagulation in patients with significant left ventricular dysfunction or pronounced apical ballooning.