Acute Cardiac Care, March 2014; 16(1): 15–22 Copyright © 2014 Informa UK, Ltd ISSN 1748-2941 print/ISSN 1748-295X online DOI: 10.3109/17482941.2013.869346

Takotsubo cardiomyopathy: A review Mahdi Veillet-Chowdhury, Syed Fahad Hassan & Kathleen Stergiopoulos

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Division of Cardiovascular Disease, Department of Medicine, Stony Brook University Medical Center, Stony Brook, NY, USA

cardiomyopathy that could not be otherwise explained (1). Prevalence of TC ranges from 0.7 to 2.5% in another similar case series (2,3). Although the majority of case series are reported from Asia and Europe, several reports from the United States have confirmed similar findings (4–6). Most patients with TC are women (7,8). In a registry of patients in Rhode Island, most patients were postmenopausal women (95%) and there was suggestion of significant clustering of reported cases during the summer months (9). While the etiology of the higher occurrence in post-menopausal women is not completely clear, reduced estrogen levels could play an important role in the pathogenesis by predisposing endothelial cells to sympathetic myocardial stunning (6). The protective effect of estrogen in TC was suggested in oopharectomized rats in which estrogen supplementation partially prevented stress-induced left ventricular dysfunction (10). The role of estrogen in this disorder remains to be fully elucidated.

Takotsubo cardiomyopathy can occur after acute mental or physical stress, subarachnoid hemorrhage, ischemic stroke, major head trauma, acute medical illness or acute pheochromocytoma crisis. It is characterized by transient systolic dysfunction of the apical and/or midventricular segments in patients without epicardial coronary artery disease. The condition occurs most commonly in postmenopausal women, and is characterized by transient left ventricular dysfunction. The pathophysiology of the disorder remains to be elucidated but may involve catecholamine excess and vasospasm. Future studies, perhaps in the form of an international registry, may clarify the incidence, pathophysiology, clinical course, and prognosis of this disorder. Keywords: Takotsubo cardiomyopathy, apical ballooning synd-

rome, review

Introduction Takotsubo cardiomyopathy (TC) or apical-ballooning syndrome is an increasingly recognized disorder characterized by acute reversible apical ventricular dysfunction in the absence of epicardial coronary disease. The heart takes on the appearance of a Japanese octopus fishing pot called a ‘takotsubo’, in which there is apical ballooning with a relatively narrow neck. TC is more common in post-menopausal women and occurs soon after exposure to sudden, unexpected emotional or physical stress. The current thinking behind the demographics, epidemiology, pathophysiology and prognosis are still evolving. This review summarizes the current thinking regarding this perplexing condition.

Pathophysiology The precise mechanism(s) of TC have not been fully elucidated. The proposed mechanisms of this unique syndrome of reversible cardiomyopathy include: (1) epicardial coronary artery vasospasm; (2) coronary microvascular impairment; (3) direct catecholamine-induced myocyte injury and/or (4) neurogenic stunned myocardium. These potential mechanisms may not be mutually exclusive, but rather there is likely a strong interplay between the autonomic, neurologic and cardiovascular systems. Patients who have undergone myocardial biopsy have demonstrated the presence of contraction bands with or without frank myocyte necrosis, myocardial fibrosis, interstitial infiltrates consisting of mononuclear lymphocytes, leukocytes and macrophages consistent with an inflammatory response. The findings of contraction bands and inflammation distinguish TC from acute myocardial infarction, where coagulation necrosis would predominate.

Scope of the problem TC mimics the clinical presentation of acute myocardial infarction. In patients undergoing cardiac catheterization for acute myocardial infarction, there is an approximately 1% incidence of this disorder (1). In a study of patients with suspected acute coronary syndrome and elevated cardiac enzymes who underwent a left heart catheterization, approximately 1.2% of patients were identified as having transient

Multi-vessel epicardial coronary artery vasospasm Several authors have proposed that multi-vessel epicardial coronary artery vasospasm causing ischemia is responsible

Correspondence: Kathleen Stergiopoulos, Department of Medicine, Division of Cardiovascular Disease, HSC T-16 080, Stony Brook University Medical Center, Stony Brook, NY 11974–8167, USA. Tel: ⫹ 1 631 444 1066. Fax: ⫹ 1 631 444 1054. E-mail: [email protected] (Received 13 September 2013; accepted 18 November 2013)


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for reversible left ventricular dysfunction (11,12). However, the data supporting this theory has been limited. Few patients have demonstrable vasospasm with provocative challenges (11,13–16). When no spontaneous coronary vasospasm occurs or is observed, it has been proposed that impaired blood flow may be due to vulnerable plaque rupture with rapid endogenous thrombolysis and reperfusion. However, multi-vessel vasospasm and regionally stunned myocardium is inconsistent with the minimal troponin elevation that is usually observed. Pathologically, the characteristic changes of ischemic stunning at the cellular level are different that those observed in patients with TC (17). Electrocardiographic (ECG) changes in acute coronary syndrome are different than those observed in TC, with the latter notable for an absence of reciprocal changes (18). However, electrocardiographic changes are insufficient to make or exclude the diagnosis. Others have proposed that short episodes of multi-vessel vasospasms might explain the reversible nature of the myocardial stunning and the usually large territory of myocardium involved. Microvascular coronary impairments Evidence suggests that coronary microvascular impairment plays a role in TC. In patients with transient left ventricular dysfunction, it has been noted that coronary microcirculation was impaired by the thrombolysis in myocardial infarction (TIMI) trial frame count (4,15). Difference in apical myocardial fatty acid metabolism in comparison to apical perfusion abnormalities has been demonstrated, which supports the concept of myocardial ‘stunning’ in the territories of wall motion abnormalities (15). Similarly, Elesber et al., demonstrated abnormal myocardial perfusion in 69% of TC patients using the TIMI myocardial perfusion grade and perfusion abnormalities involving multiple coronary territories in 86% of the patients (19). Interestingly, the authors noted a strong relationship between the severity of microvascular dysfunction and the severity of myocardial injury. Furthermore, coronary micovascular impairment has been suggested using positron emission tomography (PET) in patients with TC (20–22). One study by Kurowski et al., examining apical and mid-ventricular variants of TC patients assessed microvascular dysfunction by scintigraphy and PET studies (1). These investigators found that myocardial glucose metabolism was affected to a greater degree than was the perfusion in the impaired territories, a so-called inverse perfusion-metabolism mismatch, consistent with stunned myocardium. It may be due to an exaggerated sympathetic surge, which may mediate insulin resistance and inhibit the intracellular translocation of GLUT-4 glucose transporter, ultimately causing decreased glucose uptake (23). Decreased coronary flow velocity reserve and a short deceleration time of diastolic velocity have been observed in the acute phase in TC patients, but returned to normal after several weeks (24). The coronary flow velocity reserve and deceleration time of diastolic velocity reflect the degree of coronary microvascular dysfunction under stable hemodynamic conditions when epicardial coronary stenosis is absent (25–29).

A related theory on the etiology of TC is the hypothesis that myocardial stunning is due to rupture of an atherosclerotic plaque, which temporarily occludes the left anterior descending artery. Ibanez et al., suggested that in TC, there is a variant left anterior descending artery that extends apically and diaphragmatically (30). A plaque rupture in the middle portion could lead to an acute coronary syndrome with early reperfusion and, therefore, left ventricular stunning and only mild cardiac biomarker elevation. However, this theory would not explain the extensive regional wall motion abnormalities seen in classic or variant TC. Microcirculatory abnormalities may accompany TC; however, it is unclear how these abnormalities result either directly or indirectly in extensive wall motion abnormalities. Future studies are required to address mechanistic questions regarding this issue. Catecholamine-induced myocyte injury TC, often following emotional stress, triggers the sympathetic nervous system. Both epinephrine and norepinephrine have been reported to be markedly elevated in TC patients, which may contribute to the transient left ventricular myocardial stunning (1,6,7,31). Furthermore, patients with pheochromocytoma are known to have high levels of catecholamines and may develop a reversible cardiomyopathy (32,33). The proposed explanation for this relationship could be the result of increased intracellular concentrations of calcium in cardiac myocytes and the formation of deleterious free radicals. Endomyocardial biopsy revealed mononuclear cell infiltrates and contraction band necrosis, which is consistent with findings seen in other studies that indicate catecholamine cardiotoxicity (13,34). These findings may be due to calcium overload, resulting in ventricular dysfunction. In addition, elevated levels of catecholamines may cause coronary macro- and microcirculation vasospasms (4,35,36). The different morphologic left ventricular variants of TC could be partly explained by the differential distribution of adrenergic receptors and/or increased sensitivity of the receptors to the circulating catecholamines in certain regions of the heart (37,38). Murine studies have shown that high concentrations of epinephrine stimulates a negative inotropic effect on myocyte contraction by switching the coupling of β2 adrenoreceptors on the myocardium from Gs to a Gi protein signaling, which could cause the observed wall motion abnormalities with the highest receptor density (39). Neurogenic stunned myocardium Related to the presence of excess catecholamines in TC is the theory of neurogenic stunning of the myocardium. It has been shown that the left ventricular dysfunction and histopathological findings seen in TC are similar to that seen in subarachnoid hemorrhage (40–42). Both problems may reflect activation of the central neurogenic mechanisms. However, typically the basal segments of the left ventricle is affected while the apex is spared in subarachnoid or intracranial hemorrhage (43,44), although the reverse finding has also been reported (45,46). In addition, increased catecholamine Acute Cardiac Care

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Table I. Characteristics of patients with takotsubo cardiomyopathy from 2007 to 2012.

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Author, year (ref.) Akashi, 2007 (57) Bybee, 2007 (58) Fujiwara, 2007 (59) Lee, 2007 (60) Mitchell, 2007 (61) Burgdorf, 2008 (62) Fazio, 2008 (63) Gerbaud, 2008 (64) Meimoun, 2008 (65) Winchester, 2008 (66) Barker, 2009 (67) Eitel, 2009 (68) Leurent, 2009 (69) Regnante, 2009 (9) Sharkey, 2009 (70) Singh, 2010 (71) Sharkey, 2010 (8) Eitel, 2011 (72) Parodi, 2011 (73) Waldenborg, 2011 (74) Kosuge, 2012 (75)


Women (%)

Age (years)

ST elevation (%)

EF (%)

Troponin (I or T)

No significant CAD (%)

10 18 11 10 22 50 40 15 12 31 9 38 176 70 41 114 136 256 116 13 34

80 100 100 60 100 94 85 80 92 90 89 94 95 95 100 93 96 89 91 100 85

70 72 73 55 62 10 68 68 68 65 68 73 68 67 65 66 68 69 73 70 70

– 89 55 70 59 54 70 – 42 39 67 – – 41 – 21 49 42 60 – –

– 37.8 – 40 28 44 42 43 40 37.5 32.7 48 39.3 37 32 41 32 48 36 51 41

4.57 – 4.9 – 4.07 1.5 – 9.9 0.6 2.9 4.91 – 6.04 6.9 – 0.68 0.6 – – 2.7 –

100 100 100 100 100 100 – 100 100 71 100 100 – 100 100 100 – 94 100 100 100

increase has been linked to convulsive status epilepticus (47) and in tonic–clonic seizures (48). Naganuma et al., discussed the role of stimulation of the temporal lobe in the setting of even a partial seizure as a cause of TC, possibly by proximity of the temporal and insular cortex, and their influence on the autonomic modulation on the heart (49). The available data cannot define the mechanism of this disorder. It may be the result of catecholamine excess, in combination with differential expression and sensitivity of receptors, calcium overload, and/or a component of vasospasm. Future studies will be required to determine the details of the mechanism(s).

Diagnostic criteria While no consensus on the diagnostic criteria for TC exists, the most widely accepted diagnostic criteria have been proposed by the Mayo Clinic (50). Their suggested diagnostic criteria are the presence of all of the following features: (1) transient hypokinesis, akinesis or dyskinesis in the left ventricular mid segments with or without apical involvement; regional wall motion abnormalities that extend beyond that expected from a single epicardial vascular distribution; and frequently but not always a stressful trigger; (2) the absence of obstructive coronary artery disease or angiographic evidence of acute plaque rupture; (3) new ECG abnormalities (ST-segment elevation and/or T-wave inversion; (4) the absence of pheochromocytoma and myocarditis or other reason for left ventricular dysfunction (50). Worldwide agreement on the diagnostic criteria of TC is required for the purposes of classification, management, and prognosis. © 2014 Informa UK, Ltd.

Clinical features and clinical course Most reports have noted a clear gender discrepancy in TC, with the syndrome noted to be more common in women. The syndrome is usually preceded by acute physical or emotional stressors, such as an unexpected death in the family, abuse, a quarrel, or exhausting work. Other precipitants of TC are acute intracranial events (intracranial bleeding), head trauma, ischemic stroke, acute medical illness including sepsis, surgical procedures, overproduction of endogenous catecholamines as in pheochromocytoma or administration of exogenous catecholamines agents such as inhaled beta agonists, methylxanthines, epinephrine/ amphetamines, or cocaine (51). The identification of a preceding stressor ranged from 14–100% of cases with a preceding emotional trigger in 11–100% of cases (7). Seizures can also be associated with TC (52). In some cases, a trigger is not clearly identified. The most common complaints of patients with TC are chest pain and dyspnea, simulating an acute myocardial infarction. Other less common symptoms may include syncope, ventricular fibrillation and cardiac arrest (4,19,53). Mitral regurgitation of variable magnitude may be present, and is often transient (54).

Table II. Phenotypic left ventricular variants of takotsubo cardiomyopathy. · Apical and midventricular LV dysfunction · Isolated midventricular and basal LV dysfunction/isolated midventricular LV dysfunction (apical-sparing TC) · Isolated basal LV dysfunction · Global LV hypokinesis · Other noncoronary distribution wall motion abnormalities LV, left ventricular; TC, takotsubo cardiomyopathy (51).

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The most common findings on the admission ECG are ST-segment elevation and T-wave inversions. ST-segment elevation occurs in 59–100% of patients with ST-segment elevation in the precordial leads are the most common (Table I) (7). The presence of pathologic Q-waves ranges from 6–31% of patients (2,3). Thus, distinguishing true acute myocardial infarction from TC is difficult solely on the basis of clinical and electrocardiographic data. Although diagnostic coronary angiography is the single best tool to diagnose this condition, this disorder remains a diagnosis of exclusion. Not all TC strictly involves dysfunction of the apical segments of the left ventricle. Morphologic variants are summarized on Table II. Variants of this syndrome have been reported that involve only the mid-ventricular or basal segments (Figures 1–3) (51,55). An atypical pattern of segmental dysfunction confined to the mid-ventricle was reported in about one third of the patients in one small case series with TC (1). No differences in the demographic, clinical, impaired microcirculation in the coronary arteries, or overall outcomes between those with more typical or atypical variants of the syndrome (1). One possible explanation for the variant morphologies could be related to the variable distribution of adrenergic receptors on the myocardium. Patients with TC often have elevated levels of cardiac biomarkers. Troponin levels are usually only mildly elevated and do not follow the typical rise and fall patterns as seen in an acute myocardial infarction. Troponin I or T levels were elevated in 85% of patients with TC, whereas creatine kinase-MB fraction was elevated in 38% of patients (3). In one study, troponin T levels inversely correlated with initial ejection fraction. Troponin T levels greater than six or troponin I levels greater than 15 do not suggest TC (56). However, there are no generally accepted cut-off points for

troponin elevation, which would ultimately influence clinical management. Elevations of plasma BNP (brain natriuretic peptide) are often present on admission (7). The in-hospital mortality associated with TC is from 1–3% (51). Supportive care is usually all that is required because left ventricular function usually recovers quickly. However, left ventricular dysfunction may remain depressed for weeks before recovering. In the majority of cases, the left ventricular function returns within one-to-three months. Associated complications of TC are not common, but may include atrial and ventricular arrhythmias, hemodynamic instability, heart failure and cardiogenic shock (51). Patients with apical and midventricular variants can have associated dynamic obstruction with functional systolic anterior motion of the mitral valve due to the hyperdynamic basilar segments with resultant posteriorly directed mitral regurgitation. This finding is similar to mitral valve abnormalities associated with hypertrophic cardiomyopathy. Treatment in this scenario can be difficult, and may require fluids (if the respiratory status allows), beta-blocker administration, and possibly phenylephrine to increase afterload and reduce the outflow tract obstruction, which can worsen hypotension. In severe cases, pure LV pump failure can occur and may require intra-aortic balloon counter pulsation. Mechanical complications such as free wall rupture and ventricular septal defects can occur, but are considered rare. Systemic embolism related to acute left ventricular dysfunction can occur and is a relatively common cause of death.

Acute and chronic management At present, there are no clinical trial data available to guide clinical management of TC, and treatment decisions are often

Figure 1. (A,B). Echocardiographic apical four-chamber view demonstrating the midventricular variant of takotsubo cardiomyopathy. Images were obtained with echocardiographic contrast material to enhance endocardial definition, in diastole (A) and systole (B). Arrows denote hypokinesis of the midventricular segments, and an ejection fraction of 35%. This is a 50-year-old postmenopausal woman with a past medical history of diabetes mellitus, multiple sclerosis and seizure disorder, who presented with a witnessed generalized seizure. She had a mildly elevated troponin-I level of 0.42 ng/ml (normal 0.00–0.04 ng/ml) and was without complaints. A 12-lead electrocardiogram showed sinus tachycardia and one premature ventricular beat (not shown), without evidence of ST-segment elevation. A CT scan of her head was normal. Acute Cardiac Care

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Takotsubo Cardiomyopathy


Figure 2. Coronary angiography demonstrates normal epicardial coronary vessels (A,B), and an ejection fraction of 55% (C,D). Angiography was performed three days after initial presentation. These findings confirm the diagnosis of transient left ventricular dysfunction in the setting of normal coronary arteries.

Figure 3. Nuclear perfusion imaging with regadenoson stress. Regadenoson stress with technicium-99m sestamibi nuclear perfusion agent in the same patient one day prior to coronary angiography demonstrates a large reversible defect of moderate intensity of the mid to apical anterior, anteroseptal, and anterolateral segments, consistent with a partial thickness infarction with moderate ischemia. The calculated ejection fraction was 54%. This finding in the setting of clinical evidence of takotsubo cardiomyopathy is likely related to microvascular dysfunction. © 2014 Informa UK, Ltd.


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Table III. Management of patients with takotsubo cardiomyopathy. · Monitor in hospital on telemetry · Perform echocardiography or magnetic resonance imaging to assess left ventricular function, mitral regurgitation, LV mural thrombus, right ventricular function, dynamic LV outflow tract obstruction · Consider anticoagulation with heparin to prevent LV thrombus in patients with apical involvement if there are no contraindications to anticoagulation · Consider anticoagulation with warfarin in patients with persistent apical LV dysfunction at time of hospital discharge · Standard therapy for LV dysfunction including beta-blockers, angiotensin converting enzyme inhibition or other adrenergic blocking agent · Repeat echocardiography prior to hospital discharge to reassess LV systolic function · Consider repeat echocardiography at one-to-three months, to assess for LV recovery LV, left ventricular (51).

individualized. In the absence of consensus guidelines, Table III lists some general principles of management. Since sympathetic activation is thought to contribute to the pathogenesis of TC, it is reasonable to consider long-term beta-blocker therapy with the goal of preventing recurrence (31). Diuretics are administered as needed, but may worsen dynamic obstruction if present. The use of angiotensin-converting enzyme inhibition should be considered at least until left ventricular function recovers. The prognosis of patients with TC appears to be favorable, but long-term registry data is lacking.

Risk of recurrence Recurrence of TC has been reported. Little evidence exists on the incidence and risk of recurrence after an initial episode (5). However, some data suggests the risk of recurrence in the first few years after an initial episode may be in the range of 2–10% (2,5). It is thought that recurrence rates may be low in patients who are maintained on comprehensive beta adrenergic blockade. More information is needed in this arena to guide patients and clinicians. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Acute Cardiac Care

Takotsubo cardiomyopathy: a review.

Takotsubo cardiomyopathy can occur after acute mental or physical stress, subarachnoid hemorrhage, ischemic stroke, major head trauma, acute medical i...
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