INTRODUCTION — Stress-induced cardiomyopathy, also called apical ballooning syndrome, broken heart syndrome, and, in Japan, takotsubo cardiomyopathy, is an increasingly reported syndrome generally characterized by transient systolic dysfunction of the apical and/or mid segments of the left ventricle that mimics myocardial infarction (MI), but in the absence of significant coronary artery disease [1-12].

Takotsubo cardiomyopathy was first described in Japan [13]. Stress-induced cardiomyopathy has subsequently been reported in non-Asian populations, including the United States [4,7,8] and Europe [6,14].

The name of the disorder is taken from the Japanese name for an octopus trap (tako-tsubo), which has a shape that is similar to the apical ballooning configuration of the LV in systole in the "typical" form of this disorder. In the more commonly described "typical" type of stress-induced cardiomyopathy, the contractile function of the mid and apical segments of the LV are depressed, and there is compensatory hyperkinesis of the basal walls, producing ballooning of the apex with systole. In a minority of cases (40 percent in one report), the ventricular hypokinesis is restricted to the midventricle ("atypical") with relative sparing of the apex [14].

Stress-induced cardiomyopathy is much more common in women than men [1,2,4,12,14]. In a review of ten prospective series, women accounted for 80 to 100 percent of cases, with a mean age of 61 to 76 years [12].

PATHOGENESIS — The onset of stress-induced cardiomyopathy is frequently but not always triggered by an acute medical illness or by intense emotional or physical stress (eg, death of relatives, particularly if unexpected, domestic abuse, arguments, catastrophic medical diagnoses, devastating financial or gambling losses, natural disasters) [2-7,15].

The pathogenesis of this disorder is not well understood. Although the clinical presentation simulates that of an acute MI, coronary arteriography shows no critical lesions [2,4] and only a minority of patients display coronary spasm with acetylcholine provocation [2].

Postulated mechanisms include catecholamine excess, coronary artery spasm, and microvascular dysfunction. Catecholamine excess may lead to transient left ventricular dysfunction via microvascular spasm or dysfunction or catecholemine-mediated effects on cardiomyocytes. Alternatively, it may cause dynamic mid-cavity obstruction which may contribute to apical dysfunction. Analogous permanent (rather than transient) apical outpouchings develop in patients with hypertrophic cardiomyopathy and mid-ventricular obstruction. (See "Pathophysiology of obstructive hypertrophic cardiomyopathy", section on 'Midcavity obstructive HCM'.)

It is not known why this disorder affects women disproportionately or why the left ventricular mid-cavity and apex are predominantly affected [8].

Physical or emotional stress — A number of features of stress-induced cardiomyopathy, including its association with physical or emotional stress [2-7,15], suggest that this disorder may be caused by diffuse catecholamine-induced microvascular spasm or dysfunction, resulting in myocardial stunning [16], or by direct catecholamine-associated myocardial toxicity [17]. (See "Clinical syndromes of stunned or hibernating myocardium".)

Support for a possible pathogenic role for catecholamines comes from studies in which plasma catecholamines were measured at presentation [5,18-20]. Combining the results from these series, plasma norepinephrine levels were elevated in 26 of 35 patients (74 percent) [16]. Elevated catecholamine levels and reversible left ventricular ballooning have also been observed in an a rat model of immobilization-induced stress [21].

The magnitude of catecholamine excess associated with this disorder was illustrated in a report that measured plasma catecholamine levels in 13 patients with stress-induced cardiomyopathy and seven patients with a Killip class III MI (table 1) [5]. Plasma catecholamines were significantly higher in the patients with stress-induced cardiomyopathy as compared to those with MI: epinephrine (1264 versus 376 pg/mL) and norepinephrine (2284 versus 1100 pg/mL).

The following observations support the hypothesis of catecholamine-induced vascular dysfunction:

• The occasional finding of multifocal coronary vasospasm on coronary angiography [2,4,22].
• The frequent induction of single or multivessel coronary spasm by the intracoronary administration of ergonovine or acetylcholine [22].
• Transient myocardial perfusion abnormalities that resolve with improvement in the myopathy [18].
• The presence of abnormal TIMI frame counts on angiography [7]. The TIMI frame count is the number of cine frames required for dye to first reach standardized distal coronary landmarks. (See "Fibrinolytic (thrombolytic) agents in acute ST elevation myocardial infarction: Markers of efficacy", section on 'TIMI frame count'.)

The following observations support the hypothesis of catecholamine-induced myocardial effects:

• Similar transient LV dysfunction is sometimes seen in the setting of acute brain injury, which has also been postulated to be related to catecholamine excess [23]. (See "Cardiac complications of stroke", section on 'Neurogenic cardiac damage'.)
• Limited available endomyocardial biopsy data [3,5,17] are consistent with histologic signs of catecholamine toxicity [24,25]. Findings have ranged from no evidence of myocarditis [22] to interstitial fibrosis with or without slight cellular infiltration [3] to mononuclear infiltrates with contraction band necrosis [5]. In a series of 8 patients, acute biopsies obtained during the period of left ventricular dysfunction revealed intracellular accumulation of glycogen, many vacuoles, disorganized cytoskeletal and contractile structure, contraction bands and increased extracellular matrix proteins [17]. These alterations resolved nearly completely after functional recovery.
• In a mouse model, it has been demonstrated that a high level of epinephrine is negatively inotropic due to a switch from beta-2 adrenoreceptor mediated Gs protein signaling, which is positively inotropic, to Gi protein signaling which is negatively inotropic [26]. It is speculated that the greater effect at the apical myocardium may be due to a higher density of beta-adrenoreceptors at this location [27].

Critical illness — The incidence of stress-induced cardiomyopathy in a medical intensive care unit (ICU) population was prospectively evaluated in a series of 92 patients with a non-cardiac diagnosis and no prior history of cardiac disease [28]. All patients underwent serial echocardiography on admission and on hospital days three and seven, specifically evaluated for LV apical ballooning. The following findings were reported:

• 26 patients had LV apical ballooning (21 on admission), with an average left ventricular ejection fraction (LVEF) of 33 percent.
• Left ventricular function normalized in 20 patients at a mean of seven days.
• In multivariable analysis, sepsis was the only predictor of LV apical ballooning.
• LV apical ballooning predicted lower 2-month survival (52 versus 71 percent without this finding).

The high incidence of transient LV apical ballooning in this series requires validation in larger series, but it appears that this phenomenon is not uncommon in a medical ICU population.

PREVALENCE — The incidence and prevalence of stress-induced cardiomyopathy is uncertain. Although it was initially considered to be an uncommon disorder, it is increasingly reported in the literature and recognized in clinical practice. Some of the best available estimates come from four small series of consecutive patients presenting with a suspected acute coronary syndrome (ACS) [7,18,19,29], which were included in a larger systematic review [16]. Each of these series included 10 to 16 patients with stress-induced cardiomyopathy, accounting for approximately 1.7 to 2.2 percent of cases presenting with suspected ACS.

A similar prevalence of 1.2 percent was reported from a registry of 3,265 patients with troponin-positive ACS [14].

CLINICAL PRESENTATION — The clinical presentation of stress-induced cardiomyopathy is similar to that of an acute MI [1,2,4]. The most common presenting symptom is acute substernal chest pain, but some patients present with dyspnea, shock, or electrocardiographic abnormalities.

Acute complications of stress-induced cardiomyopathy can include tachyarrhythmias (including ventricular tachycardia and ventricular fibrillation), bradyarrhythmias, pulmonary edema, mitral regurgitation and cardiogenic shock [1,2,4,6]. In a review of 12 prospective series (with 13 to 88 subjects), pulmonary edema occurred in 0 to 44 percent of cases and intra-aortic balloon counterpulsation was used in 0 to 18 percent of patients [12]. Left ventricular outflow tract (LVOT) obstruction, induced by left ventricular basal hyperkinesis, can contribute to the development of shock and cause severe mitral regurgitation or the murmur of hypertrophic cardiomyopathy [30]. Apical thrombus formation and stroke have also been described [31]. (See "Auscultation of cardiac murmurs", section on 'Subvalvular outflow obstruction'.)

Data on the characteristics of stress-induced cardiomyopathy come from relatively small case series [1-7,18,30,32,33]. A systematic review of 14 series, including a total of 286 patients, provides a more comprehensive assessment of this disorder [16]. The range of findings from these reports is illustrated by the following:

• Electrocardiographic abnormalities are the most common finding. ST segment elevation was present in 56 percent of patients in the systematic review [33]. Among these patients, ST segment elevation was most common in the anterior precordial leads. The remaining patients had deep T-wave inversion with QT interval prolongation, abnormal Q-waves, non-specific abnormalities, and in some cases the ECG is normal at presentation [2,5,32].
• Cardiac biomarkers, specifically with high sensitivity troponin assays, are always elevated. However, the elevations are typically mild, which is inconsistent with the often severe hemodynamic compromise. In the systematic review, among studies that measured cardiac troponins or creatine kinase MB, these levels were elevated in 86 and 74 percent of patients, respectively [16].
• Left ventriculography or echocardiography usually show the characteristic apical ballooning with akinesis or dyskinesis of the apical one-half to two-thirds of the LV [1-6,16,18]. Overall systolic function is reduced, and the reported average LVEF has ranged from 20 to 49 percent [2,4,5,16]. Apical sparing variant accounts for a significant proportion of patients, though the clinical characteristics of typical and apical sparing forms appear to be similar [11,27-31]. No obvious mechanism for the different patterns of regional wall motion abnormality has been identified.
• In the systematic review, transient LVOT obstruction was reported in 16 percent of the patients (21 of 133) who underwent left ventriculography [16]. In some cases, this is accompanied by systolic anterior motion of the mitral valve, similar to that seen in hypertrophic cardiomyopathy [30].
• Reversible perfusion abnormalities in the left ventricular apex have been documented [1,3], while cardiovascular magnetic resonance imaging (CMRI) typically shows mid and apical LV segmental wall motion abnormalities, often in multiple coronary territories without delayed hyperenhancement of involved regions [4,34].

Diagnosis — The diagnosis of stress-induced cardiomyopathy should be suspected in postmenopausal women who present with an acute coronary syndrome after intense psychologic stress in whom the clinical manifestations and ECG abnormalities are out of proportion to the degree of elevation in cardiac enzymes [8]. Apical ballooning or midventricular hypokinesis is usually seen on left ventriculography or echocardiography [1-4,6,14,18]. In a minority of cases (40 percent in one report), transient left ventricular hypokinesis is midventricular ("atypical") rather than apical ("typical) [14].

Coronary angiography, by definition, reveals no critical coronary lesions. However, in addition to stress-induced cardiomyopathy, a number of other syndromes have been associated with ST segment changes in the absence of significant coronary artery disease, including cardiac syndrome X, variant (Prinzmetal's) angina, myocarditis, and cocaine abuse. These topics are discussed in detail separately. (See "Cardiac syndrome X: Angina pectoris with normal coronary arteries", section on 'Acute coronary syndrome' and "Variant angina" and "Clinical manifestations and diagnosis of myocarditis in adults" and "Cardiovascular complications of cocaine abuse".)

The following are the proposed Mayo Clinic diagnostic criteria, all four of which are required for the diagnosis [1,11]:

• Transient hypokinesis, akinesis or dyskinesis of the left ventricular mid segments with or without apical involvement. The regional wall motion abnormalities typically extend beyond a single epicardial coronary distribution. A stressful trigger is often, but not always present.
• Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture.
• New electrocardiographic abnormalities (either ST-segment elevation and/or T- wave inversion) or modest elevation in cardiac troponin.
• Absence of pheochromocytoma or myocarditis.

There are rare exceptions to these criteria such as patients in whom the regional wall motion abnormality is limited to a single coronary territory, and the occasional patient with obstructive coronary atherosclerosis who develops stress-induced cardiomyopathy.

An important issue is how the possible diagnosis of stress-induced cardiomyopathy should influence the evaluation of a suspected acute coronary syndrome. We suggest the following approach:

• Patients presenting with ST elevation who can undergo urgent cardiac catheterization for the purpose of primary PCI should proceed with angiography in the usual manner. If the patient has stress-induced cardiomyopathy, angiographic findings will suggest the diagnosis by showing no critical coronary disease and the presence of apical ballooning (or mid wall hypokinesis) on left ventricular angiography. (See "Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Therapeutic use".)

• Patients presenting with ST elevation, but for whom urgent angiography and PCI are not available are usually treated with fibrinolytic therapy. In such cases, suspicion of the diagnosis of stress-induced cardiomyopathy is not a sufficient reason to withhold fibrinolytic therapy since the majority of ST elevation presentations will be due to a critical coronary lesion. (See "Fibrinolytic (thrombolytic) agents in acute ST elevation myocardial infarction: Therapeutic use".)

In the later scenario, the diagnosis of stress-induced cardiomyopathy may later be suggested by such clinical features as the absence of critical stenoses on coronary angiography, modest cardiac enzyme elevations and recovery of LV function. However, none of these features is diagnostic, as they may also reflect successful early fibrinolysis.

• Patients who present without ST elevation will usually fit into a "high risk" NSTEMI profile (positive troponin, elderly, significant left ventricular dysfunction). Early (less than 48 hours) cardiac catheterization will be performed in most such patients, which should suggest the correct diagnosis. (See "Coronary arteriography and revascularization for unstable angina or non-ST elevation acute myocardial infarction".)

• Patients for whom both cardiac catheterization and thrombolytic therapy are relatively contraindicated are problematic. In these patients, the pattern of wall motion abnormality may differ between individuals with stress-induced cardiomyopathy and those with acute obstruction of flow in the left anterior descending coronary artery. The former had significantly more dysfunction of the right ventricular free and left ventricular lateral walls than the latter in a small, retrospective echocardiographic study [35]. The wall motion abnormalities in stress-induced cardiomyopathy typically involve the distribution of more than one coronary artery.

Right ventricular involvement — Most reports of stress-induced cardiomyopathy have focused on transient dysfunction of the left ventricle. However, there is emerging evidence that the right ventricle (RV) is also affected in some cases [36,37].

The frequency and significance of RV involvement was illustrated in a series of 34 patients with stress-induced cardiomyopathy who underwent cardiac magnetic resonance (CMR) imaging [37]. Nine patients (26 percent) had RV wall motion abnormalities. Patients with RV dysfunction had lower LV ejection fractions compared to patients with normal RV function (40 versus 48 percent), and were also more likely to have pleural effusions. At a mean of one year after presentation, follow-up CMR showed improvement or resolution of RV dysfunction in eight of nine patients.

TREATMENT AND PROGNOSIS — Despite the severity of the acute illness, stress-induced cardiomyopathy is a transient disorder managed with supportive therapy. Conservative treatment with hydration and resolution of the physical or emotional stress usually results in rapid resolution of symptoms and ECG changes.

General therapy — Once the diagnosis of stress-induced cardiomyopathy has been made, therapy is based upon the patient's overall clinical condition. There are no controlled data to define the optimal medical regimen, but it is reasonable to treat these patients with standard medications for left ventricular systolic dysfunction. These include ACE inhibitors, beta blockers, and diuretics as necessary for volume overload [1]. Aspirin is also suggested in the presence of coexisting coronary atherosclerosis [1,11]. (See "Overview of the therapy of heart failure due to systolic dysfunction".)

Stress-induced cardiomyopathy is a transient disorder. In the absence of clinical trial data, the appropriate duration of therapy is not known. We usually treat patients with the standard HF medical regimen until there is recovery of systolic function which occurs in 1-4 weeks in most cases. However, because the condition may recur, we often continue adrenergic blockade with either beta-blockers or combined alpha and beta-blockers indefinitely in the absence of contraindications or intolerance.

Hypotension and shock — Patients who are in shock should undergo urgent echocardiography to determine if left ventricular outflow tract (LVOT) obstruction is present, which has been described in 13 to 18 percent of cases [1,30].

Without left ventricular outflow tract obstruction — Patients without significant LVOT obstruction who are hypotensive due to pump dysfunction can be treated with inotropes such as dobutamine and dopamine. They may also benefit from intra-aortic balloon counterpulsation (IABP) [4].

In a patient with hypotension due to pump failure, inotropic agents may induce LVOT obstruction, but the degree is usually mild [4]. A change in the therapeutic approach is not necessary in such cases.

With left ventricular outflow tract obstruction — In contrast to hypotension due only to pump failure, hypotension associated with LVOT obstruction should NOT be treated with inotropic agents, because they can worsen the degree of obstruction [4,30].

The recommended approach to patients with moderate-to-severe LVOT obstruction includes the use of beta blockers, which can improve hemodynamics by causing resolution of the obstruction. (See "Medical therapy in hypertrophic cardiomyopathy".) In addition, in the absence of significant pulmonary congestion, the patient should be fluid resuscitated [1,30].

As with patients in shock due to pump failure, those with LVOT obstruction may benefit from an IABP, although there is a slight risk that afterload reduction from the IABP will worsen the degree of obstruction [4]. The initial treatment in such patients, however, should be to treat the underlying pathophysiological mechanisms with fluid replacement, beta blockers, and other negative inotropic agents. In patients with hypotension, whether with or without significant LVOT obstruction, who do not respond to initial medical therapy and volume resuscitation, we suggest the use of an IABP.

In patients with LVOT obstruction and severe hypotension who either do not tolerate or do not adequately respond to beta blockers, an alpha agonist may be added with caution and close monitoring. Phenylephrine is a pure alpha-adrenergic agonist that may reduce the gradient by increasing afterload, thereby improving overall hemodynamics. This treatment may be helpful to support blood pressure while a beta blocker is administered to reduce inotropy. However, the vasoconstrictive effects of alpha agonists may be harmful, particularly in these patients who can be prone to coronary vasospasm. Thus, if phenylephrine is used, it should be done with a high degree of caution and very close monitoring of hemodynamics, tissue perfusion, and mentation.

Prognosis — In-hospital mortality rates have ranged from 0 to 8 percent [1,2,4,12]. There was one in-hospital death and one late death in the largest prospective series of 88 patients in Japan [2]. Patients who survive the acute episode typically recover normal ventricular function within one to four weeks [2,4-6,22]. In two series, for example, the mean LVEF increased from 29 percent at presentation to 63 percent at a mean of six days [4] and from a median of 20 percent at presentation to 60 percent at two to four weeks [5].

The longest follow-up data comes from a study of 100 patients. Over a mean follow-up of 4.4 ± 4.6 years, 31 patients continued to have episodes of chest pain and 10 patients had recurrence of apical ballooning syndrome. Seventeen patients died, but there was no difference in survival compared to an age- and gender-matched population [38].

SUMMARY AND RECOMMENDATIONS — Stress-induced cardiomyopathy is an increasingly reported syndrome characterized by transient apical LV dysfunction in the absence of significant coronary artery disease.

• Stress-induced cardiomyopathy is typically triggered by an acute medical illness or by intense emotional or physical stress, although a triggering event is not always present. Postulated pathogenic mechanisms include catecholamine excess, multivessel coronary artery spasm, and microvascular dysfunction. (See 'Pathogenesis' above.)

• Stress-induced cardiomyopathy may account for approximately 2 percent of suspected acute coronary syndromes. (See 'Prevalence' above.)

• Common presenting features include ECG abnormalities (often anterior ST elevations), elevated cardiac biomarkers, substernal chest pain, and dyspnea. (See 'Clinical presentation' above.)

• Proposed diagnostic criteria include presence of transient regional wall motion abnormalities (typically not in a single coronary distribution), absence of angiographic evidence of obstructive coronary disease or acute plaque rupture, presence of new ECG abnormalities or modest troponin elevation, AND absence of pheochromocytoma or myocarditis. (See 'Diagnosis' above.)

• Acute complications of stress-induced cardiomyopathy include tachyarrhythmias, bradyarrhythmias, pulmonary edema, cardiogenic shock, and transient LVOT obstruction. (See 'Clinical presentation' above.)

• In-hospital mortality ranges from 0 to 8 percent. Patients who survive the acute episode typically recover normal LV function within one to four weeks. (See 'Prognosis' above.)

Management — The initial management of stress-induced cardiomyopathy is largely supportive, including hydration and an attempt to alleviate the triggering physical or emotional stress. The role of additional medications and the appropriate duration of therapy is not established. Most experts favor at least the short-term use of standard medications for heart failure due to systolic dysfunction. (See "Overview of the therapy of heart failure due to systolic dysfunction".)

• In patients who present with a clinical picture consistent with an ST elevation MI, the suspicion of stress-induced cardiomyopathy is not a reason to alter management. The significant majority of these cases are due to occlusion of a coronary artery and revascularization therapy should not be delayed. We recommend that such patients be managed in the conventional manner, either with urgent catheterization and PCI or with fibrinolytic therapy (Grade 1B). (See "Criteria for the diagnosis of acute myocardial infarction" and "Selecting a reperfusion strategy for acute ST elevation myocardial infarction".)

We approach hemodynamically stable patients diagnosed with stress-induced cardiomyopathy in the following manner (see 'General therapy' above:

• We suggest the initiation of a beta blocker (Grade 2C).
• In patients who do not have an LVOT gradient, we suggest the initiation of an ACE inhibitor or an angiotensin receptor blocker (Grade 2C).
• In patients with heart failure who do not have an LVOT gradient, we suggest diuresis (Grade 2C).
• We suggest treatment with aspirin in the presence of coexisting coronary atherosclerosis (Grade 2C).

Hypotension and shock — Some patients with stress-induced cardiomyopathy will develop hypotension and shock, which could be due either to severe systolic dysfunction or to LVOT obstruction. Because it will influence the choice of treatment, patients who develop severe hypotension should undergo urgent echocardiography to determine if LVOT obstruction is present.

• In patients with hypotension, whether with or without significant LVOT obstruction, if significant pulmonary congestion is not present we suggest cautious fluid resuscitation (Grade 2C). (See 'Hypotension and shock' above.)

• In patients with hypotension who do not have significant outflow obstruction, we suggest intravenous inotropes, such as dopamine (Grade 2C). (See 'Hypotension and shock' above.)

• In patients with hypotension and moderate-to-severe LVOT obstruction, we suggest that inotropic agents not be used because they can worsen the degree of obstruction (Grade 2C). (See 'Hypotension and shock' above.)
• In patients with hypotension and moderate-to-severe LVOT obstruction, we suggest beta blockers, which can improve hemodynamics by causing resolution of the obstruction (Grade 2C). In patients with LVOT obstruction and severe hypotension who either do not tolerate or do not adequately respond to beta blockers, an alpha agonist may be added with caution and close monitoring. (See 'Hypotension and shock' above.)

• In patients with hypotension, whether with or without significant LVOT obstruction, who do not respond to initial medical therapy and volume resuscitation, we suggest the use of an IABP (Grade 2C). (See 'Hypotension and shock' above.)