Takotsubo Cardiomyopathy: A Unique Cardiomyopathy With Variable Ventricular Morphology 
J Am Coll Cardiol Img. 2010;3(6):641-649. doi:10.1016/j.jcmg.2010.01.009
Abstract
Takotsubo cardiomyopathy is an important differential diagnosis of acute coronary syndrome. It is characterized by normal (or near-normal) coronary arteries, regional wall motion abnormalities that extend beyond a single coronary vascular bed, and often, a precipitating stressor. Variants of the classical left ventricular apical ballooning, including mid- or basal left ventricular wall motion abnormalities, are increasingly recognized. Takotsubo cardiomyopathy is not rare, and heightened awareness of this unique cardiomyopathy likely will lead to a higher reported incidence. Diagnosis of takotsubo cardiomyopathy has important implications for clinical management at presentation and afterward. The long-term prognosis is generally favorable; however, a small subset has potentially life-threatening complications during the initial presentation. The pathophysiologic mechanism is unknown, but catecholamine excess likely has a central role.
Takotsubo cardiomyopathy is a novel cardiomyopathy that has been recently recognized as an important consideration in the differential diagnosis of acute coronary syndrome. The presenting features of takotsubo cardiomyopathy are similar to those of myocardial ischemia after acute plaque rupture, but the characteristic distinctions are regional wall motion abnormalities that extend beyond a single coronary vascular bed and the absence of epicardial coronary occlusion. A preceding emotional or physical stressor is common. Although the acute presentation can include life-threatening symptoms and hemodynamic compromise, the long-term prognosis is more benign than that of traditional acute coronary syndrome (1-6). Although this cardiomyopathy classically is described as “apical ballooning syndrome,” emerging data show variant forms that include isolated basal, mid-ventricular, or apical segment involvement. The pathophysiology underlying takotsubo cardiomyopathy is not known, but the most compelling evidence suggests a catecholamine excess.
Takotsubo cardiomyopathy first was described in a case series of 5 Japanese patients in 1991 (7). The name of the syndrome was coined (8) on the basis of similarities between the appearance of the left ventricle in systole (narrow neck and wide base; Figure 1A and Figure 1B) and the shape of a Japanese octopus trap. Other suggested names are “transient ventricular ballooning syndrome,” “left ventricular apical ballooning syndrome,” “stress-induced cardiomyopathy,” “ampulla cardiomyopathy,” and “broken heart syndrome.”
Figure 1
Radiograph of the Left Ventricle
(A) Left ventriculogram in diastole. (B) Left ventriculogram in systole shows preserved contraction of the base of the ventricle and apical ballooning. (C) Right anterior oblique view in diastole. (D) Right anterior oblique view in systole. Note the hypercontractility of the basal and apical segments and ballooning of the mid-ventricular segments. (E) After methamphetamine use in end-diastole. (F) After methamphetamine use in end-systole. Basal segments are akinetic, the papillary level shows normal contractility, and the apex is hypercontractile. (G) Cardiac magnetic resonance image. Hypotension may be due to dynamic outflow tract obstruction caused by hyperkinesis of the basal left ventricle segments and systolic anterior motion of the mitral valve. Four-chamber, steady-state, free-precession image: end-diastole (left) and end-systole (center) show left and right ventricular apical akinesis.(Right) Three-chamber image in systole shows systolic anterior motion of the mitral leaflets (*) with dynamic left ventricular outflow tract obstruction; left ventricular apical mass consistent with thrombus(**). Panels C and D are adapted, with permission from Hurst et al. (31). Panels E and F are adapted, with permission from Reuss et al. (34). Panel G is adapted, with permission from Syed IS, et al. (38). Apical ballooning syndrome or aborted myocardial infarction? Insights from cardiovascular magnetic resonance imaging. Int J Cardiovasc Imaging 2008;24:875–82. Ao = aorta; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.
Patient characteristics
Takotsubo cardiomyopathy represents an estimated 1% to 2% of patients who present with an acute coronary syndrome (1), although this estimate may be low because of under-recognition. The age range of patients with takotsubo cardiomyopathy extends from the first to the ninth decade (4), and patients are usually female and most commonly post-menopausal, whereas men account for less than 10% of cases. In the first large Japanese series describing takotsubo cardiomyopathy, 76 patients were women, 12 were men, and the median age was 67 ± 13 years (4). Forty-three percent had a preceding acute medical condition (surgical procedure, cerebrovascular accident, asthma exacerbation), and 27% had a severe emotional or physical stressor. The in-hospital course was complicated by pulmonary edema (22%), cardiogenic shock (15%), ventricular tachycardia or fibrillation (9%), or death (1%). However, 85 of 88 patients were New York Heart Association functional class I at discharge, with a mean left ventricular ejection fraction that improved from 41% ± 11% at admission to 64% ± 10% at discharge. During a mean follow-up of 13 ± 14 months, 2 patients had recurrence and 1 had sudden death. Similar findings have been reported in subsequent case series from around the world, including Europe (9) and the U.S. (1,6).
Presentation
The most common presenting symptom is chest pain (70% to 90%). Less common symptoms such as dyspnea (approximately 20%) and pulmonary edema may occur, but cardiac arrest, cardiogenic shock, and serious ventricular arrhythmias are rare (4,6,10-11). Nonspecific symptoms such as syncope, weakness, cough, and fever also have been reported (12). An emotional, psychological, or physical stressor (or a combination) is typical, although not always present (1). Commonly reported precipitating stressors include being informed of the death of a loved one, social events such as public speaking or a surprise birthday party, and anxiety or pain related to a medical procedure (1-6,9). Other situations that are less common, but still considered possible triggers of takotsubo cardiomyopathy, include cocaine use (13), opiate withdrawal (14), stress testing (15) (with dobutamine [16]), lightning strike (17), ergonovine injection (18), and thyrotoxicosis (19). A chronobiological pattern has also been reported by a multicenter Italian study, with increased frequency of presentation in the summer months and in the morning hours (20). As our experience and knowledge of takotsubo cardiomyopathy has increased, the proposed Mayo diagnostic criteria for the syndrome have evolved. Table 1 shows updated criteria (21).
Takotsubo cardiomyopathy should be considered in the differential diagnosis of acute myocardial infarction for a post-menopausal woman who presents with symptoms of myocardial ischemia after acute emotional or physical stress. For such patients, emergent transfer to a center with primary angioplasty capabilities may lead to the diagnosis of takotsubo cardiomyopathy, thereby avoiding the administration of fibrinolytic therapy and the potential, subsequent complications. However, such transfers should only be considered when transfer and angiography can be performed within recommended door-to-balloon guidelines (22). Furthermore, such a strategy must not be implemented at the expense of withholding life-saving reperfusion therapy from patients with ST-segment elevation myocardial infarction.
Electrocardiography, coronary angiography, and left ventriculography
Electrocardiogram findings in patients with takotsubo cardiomyopathy vary at presentation. ST-segment elevation is present in approximately one-third of patients, with the anterior leads most commonly involved (Figure 2) (23-24). However, deep T-wave inversion and nonspecific ST-T wave changes may also be seen on the electrocardiogram at presentation. Common changes observed with serial electrocardiograms include prolongation of the QT interval and deep, symmetric T-wave inversion (1,3) that may take several weeks or months to resolve (Figure 2) (12,25). Despite the long QT interval, torsades de pointes rarely is reported (26-27). Individuals who present with ST-segment elevation have a higher likelihood of undergoing coronary angiography, which is required for the diagnosis of takotsubo cardiomyopathy. Thus, the high percentage of patients with takotsubo cardiomyopathy and ST-segment elevation in some series may be due to selection bias.
Figure 2
Longitudinal Left Ventricular Strain in Stress Cardiomyopathy
A 73-year-old woman presented with chest pain and normal coronary arteries (as determined by coronary angiography). End-systolic (A) and end-diastolic (B) frames are diagnostic of apical ballooning syndrome. Bull's-eye view of left ventricle shows longitudinal strain on day 1 (C) and day 2 (D). Contracting segments are in red, akinetic and dyskinetic segments are in blue. Note the early appearance of red in basal and mid-ventricular segments of the inferior wall and septum, indicating recovery of myocardial shortening strain on day 2. ANT = anterior; ANT_SEPT = anterior septal; INF = inferior; LAT = lateral; POST = posterior; SEPT = septal.
The absence of obstructive coronary artery disease or evidence of acute plaque rupture has been proposed as a diagnostic criterion (23). However, there is no reason that an individual with established, stable coronary artery disease would not also be at risk of having takotsubo cardiomyopathy. A recent case series of 97 Japanese patients with takotsubo cardiomyopathy noted a 10% incidence of incidental coronary artery disease (>75% stenosis of a major epicardial coronary artery) (28). Another case series described 7 patients with presentations consistent with takotsubo cardiomyopathy, and at least 1 epicardial coronary artery with 50% or greater stenosis (29). In our experience, severe coronary stenosis is uncommon, and when identified in patients with takotsubo cardiomyopathy, it is rarely in a multivessel distribution (30).
Classically, the apical or mid-ventricular segments (or both) of the left ventricle are akinetic (Figure 3). However, other patterns of left ventricular wall motion abnormality have been reported. Takotsubo cardiomyopathy with mid-ventricular akinesis and apical sparing has been described (Figure 1C and Figure1D) (31-32) and may not be uncommon. A recent report suggested that as many as 40% of patients with takotsubo cardiomyopathy have a mid-ventricular variant (33). Basal akinesis with mid-ventricular and apical sparing (Figure 1E and Figure 1F) also has been reported (34). We have occasionally noted a changing pattern of wall motion abnormality (i.e., from mid-ventricular to apical variant) in the same patient, as have other investigators (35).
Figure 3
Short-Axis Images From a Patient With Takotsubo Cardiomyopathy at 2 Days and 6 Weeks After Presentation With Stress-Induced Cardiomyopathy
(A) Myocardial blood flow (13N-ammonia). (B)11C hydroxyephedrine positron emission tomography shows preserved perfusion but transiently abnormal sympathetic activity. Adapted with permission from Prasad et al. (54).
Cardiac biomarkers
Biomarkers of cardiac myonecrosis generally are elevated at presentation (1-6). This is almost always the case for cardiac troponin. Usually, the biomarker levels peak within 24 h after presentation, but the levels are markedly lower than would be anticipated on the basis of the extent of wall motion abnormalities and electrocardiogram findings. The absence of clinically significant myocardial necrosis has been confirmed in several case series in which cardiac magnetic resonance examination has shown the absence of gadolinium hyperenhancement (3).
Acute care
Initial clinical management of patients with takotsubo cardiomyopathy is similar to that of patients with acute coronary syndrome. The diagnosis must be confirmed with coronary artery and left ventricular imaging. A high index of suspicion is required because early recognition can affect management; this is particularly true when fibrinolytic therapy is being considered for patients presenting with ST-segment elevation.
Hypotension occurs frequently, and it is important to identify the cause of hypotension to determine appropriate management. Acute pump failure may require intravenous pressor support, but given the evidence of catecholamine excess in the origin of this syndrome, mechanical support with an intra-aortic balloon pump may be preferred. In addition, hypotension may be due to dynamic outflow tract obstruction caused by hyperkinesis of the basal left ventricular segments and systolic anterior motion of the mitral valve (Figure 1G) (1,36-38). In this situation, intravenous inotropic agents would be contraindicated; to reduce outflow obstruction, short-acting β-blockers (39) and intravenous fluids could be used cautiously to decrease contractility and increase cavity size, respectively. Peripheral vasoconstrictors such as phenylephrine may be considered if β-blockers and fluid administration are contraindicated or ineffective.
Right ventricular involvement in takotsubo cardiomyopathy has been reported (10,43-45), and right ventricle involvement at presentation may be an important predictor of adverse outcome. In a study of 30 patients with takotsubo cardiomyopathy (10), right ventricular dysfunction (involving apical or mid-ventricular segments [or both], similar to the left ventricle) was highly associated with longer hospitalization, severe congestive heart failure, the use of intra-aortic balloon pumps, or performance of cardiopulmonary resuscitation.
Subacute and long-term care
In-hospital death is rare (4,10); if it occurs, it may be attributable to the underlying stressor rather than to the cardiomyopathy itself (6,46). Only a relatively small number of cases of takotsubo cardiomyopathy–related death have been reported in the literature to date. The incidence of sudden death caused by takotsubo cardiomyopathy before evaluation in a hospital or emergency department is unknown, of course, but it has been described (47).
Complete recovery of left ventricular systolic function is necessary to confirm the diagnosis of takotsubo cardiomyopathy. The recovery time varies and can be as short as several days or as long as several weeks (6). Our practice uses an empirical approach, treating individuals with takotsubo cardiomyopathy as those with other causes of cardiomyopathy (with angiotensin-converting enzyme inhibitors and β-blockers), at least until left ventricular systolic function recovers. Left ventricular thrombus (6,48) and systemic thromboembolism have been reported. Anticoagulation therapy, at least until recovery of the wall motion abnormality, should be considered for those with clinically significant apical hypokinesis or akinesis that persists 2 to 3 days after presentation. Systemic thromboembolism has been reported in takotsubo cardiomyopathy (49).
Long-term β-blockade and combined α- and β-blockade are attractive therapies given the putative association between takotsubo cardiomyopathy and a catecholamine surge. Such strategies have been advocated if patients have no contraindications, but few trial data show efficacy of these strategies (32,50).
The pathophysiology of takotsubo cardiomyopathy is not established but is likely multifactorial, involving the vascular, endocrine, and central nervous systems (51). The instigating factor for most patients is an emotional or physical stressor that commonly is associated with a “fight or flight” hypersympathetic response. Most evidence suggests a major contribution from catecholamine excess and exaggerated stimulation of the sympathetic nervous system. Abraham et al. (52) described 9 cases of takotsubo cardiomyopathy precipitated by epinephrine or dobutamine infusion. All morphologic variants of takotsubo cardiomyopathy (apical, mid-, and basal) were observed, suggesting a common causality of excessive sympathetic stimulation. Wittstein et al. (3) determined that norepinephrine, epinephrine, and dopamine levels were approximately 2 to 3 times higher in patients with takotsubo cardiomyopathy than in patients with clinically significant left ventricular dysfunction due to acute myocardial infarction. Biopsy findings from the same study showed mononuclear cell infiltrate and contraction band necrosis, which are consistent with catecholamine-induced myocardial injury. In a study of 8 patients with takotsubo cardiomyopathy (53), myocardial scintigraphy with 123I-meta-iodobenzylguanidine showed evidence of cardiac sympathetic hyperactivity, which improved after 3 months. Transient abnormal cardiac sympathetic activity was also shown by 11C-hydroxyephedrine imaging with positron emission tomography (Figure 3) (54). An animal model of takotsubo cardiomyopathy with immobilized rats showed that the abnormal findings typically observed in electrocardiograms and left ventriculograms were mitigated by α- and β-blockade and partially attenuated by estrogen (55-56). More recently, increased local release of catecholamines from the hearts of patients with takotsubo cardiomyopathy has been documented (57).
It is difficult to ignore the similar cardiac manifestations of takotsubo cardiomyopathy and other disease entities with heightened catecholamine and sympathetic discharge such as subarachnoid hemorrhage (58-59) and pheochromocytoma (60-61). Animal models of subarachnoid hemorrhage have shown a correlation between catecholamine levels and the extent of myocardial damage (62). Lyon et al. (63) recently proposed that a switch in intracellular signal trafficking protects cells against proapoptotic effects of catecholamines but is negatively inotropic when the β1-adrenoceptor is intensely activated, thereby causing myocardial stunning when high levels of epinephrine are circulating. A catecholamine-induced disorder in glucose metabolism has been suggested on the basis of decreased left ventricular apical 18F-fluorodeoxyglucose uptake on positron emission tomography of 15 patients with the apical variant of takotsubo cardiomyopathy (64).
Some investigators have reported coronary microvascular dysfunction in patients with takotsubo cardiomyopathy (1,65-69), which may either cause or be caused by the sympathetic response. Mayo Clinic investigators evaluated coronary angiograms of 42 consecutive patients with takotsubo cardiomyopathy and found abnormal myocardial perfusion in 69%, as determined by Thrombolysis In Myocardial Infarction myocardial perfusion grade (70).
Myocarditis as a cause of takotsubo cardiomyopathy is not well supported by the data. Viral titers do not rise after the initial event (71), and biopsy findings are not suggestive of myocarditis (71-72). Cardiac magnetic resonance imaging of a limited number of patients has shown no evidence of myocarditis or infarction (3,6).
Multivessel epicardial coronary artery spasm as a cause of takotsubo cardiomyopathy is not strongly supported in the literature, despite isolated reports (72-73). ST segments commonly remain elevated in patients with takotsubo cardiomyopathy, even when coronary angiography shows no spasm. Spontaneous or invoked coronary artery spasm is an infrequent observation (12).
The reason why the cardiomyopathy predominately occurs in post-menopausal women is also unexplained. A unifying mechanism of disease will need to explain why women, most commonly post-menopausal women, are predisposed to takotsubo cardiomyopathy development after heightened sympathetic discharge. A deficiency in estrogen activity may have a role, as suggested by the higher incidence in post-menopausal women and the evidence of estrogen supplementation attenuating takotsubo cardiomyopathy in an animal model (56). Endothelial dysfunction may be a mechanism, given the influence of sex hormones on endothelial function (74). Interestingly, a study of 72 individuals (47% women) with subarachnoid hemorrhage reported that left ventricular wall motion abnormality occurred only in women (59). Cardiac syndrome X also is most common in post-menopausal women, and endothelial dysfunction is thought to affect the underlying pathophysiology (75-76). A genetic component is suggested by the observation of takotsubo cardiomyopathy occurrence in 2 sisters and in a mother–daughter pair (77-78).
There is no evidence documenting different pathophysiologic mechanisms in the various morphologic variants of takotsubo cardiomyopathy. A common mechanism is suggested by the finding of 2 morphologic variants in the same individual (35) and the finding of multiple morphologic variants with epinephrine or dobutamine infusion (52).
Takotsubo cardiomyopathy is important in the differential diagnosis of acute coronary syndrome. It is characterized by normal (or near-normal) coronary arteries, regional wall motion abnormalities that extend beyond a single coronary vascular bed, and often, a precipitating stressor. Variants of the classical left ventricular apical ballooning, including mid- or basal left ventricular wall motion abnormalities, are increasingly recognized. Takotsubo cardiomyopathy is not rare, and heightened awareness of this unique cardiomyopathy likely will lead to a higher reported incidence. Diagnosis of takotsubo cardiomyopathy has important implications for clinical management at presentation and afterward. The long-term prognosis is generally favorable; however, a small subset has potentially life-threatening complications during the initial presentation. The pathophysiologic mechanism is unknown, but catecholamine excess likely has a central role.
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