In recent years, the number of documented cases of takotsubo cardiomyopathy, which occurs mainly in elderly women, has been increasing all over the world. Takotsubo cardiomyopathy presents quite similar symptoms to acute anterior myocardial infarction, but with normal coronary arteries and left ventricular apical ballooning. Takotsubo cardiomyopathy has been recognised as a source of acute heart failure, lethal ventricular arrhythmia and ventricular rupture. The onset mechanism of this syndrome is still a matter of debate. In this article, we summarise previous studies and future issues regarding takotsubo cardiomyopathy.
Acknowledgement: The authors thank Ms Masayo Hori for editing this manuscript.
Sato et al. first described Takotsubo-like left ventricular (LV) dysfunction in 1990.1 The name of this syndrome comes from the Japanese for octopus fishing pot, and it has become familiar among Japanese physicians. It is also known as transient LV apical ballooning syndrome, broken heart syndrome or ampulla-shaped cardiomyopathy, but nowadays most cardiologists refer to this phenomenon as takotsubo cardiomyopathy. This kind of reversible ventricular dysfunction was considered to be due to insufficient coronary blood flow in patients with the highest age-specific incidence rate, because stunned myocardium was generally accepted as a factor.2 However, Sato et al.1 reported that reversible ventricular dysfunction often occurred during coronary spasm. These ventricular dysfunctions gained broad attention in terms of myocardial blood flow.
Pavin et al.3 described the term stress cardiomyopathy in 1997. Physicians recognised that emotional stress might cause LV dysfunction without myocardial ischaemia due to insufficient coronary blood flow. Case reports referring to LV dysfunction associated with emotional stress, normal coronary angiography and minimally increased cardiac enzymes began to be published after 2000. In 2005, stress cardiomyopathy studies4,5 established the formal concept in the field of cardiology and/or internal medicine in developed countries. Stress cardiomyopathy is the preferred name among western physicians. The number of publications concerning this syndrome has increased to a remarkable degree in recent years (see Figure 1).
No validated criteria have been formulated for takotsubo cardiomyopathy. However, in the last five years expert consensus on the diagnostic criteria for this syndrome has been reached. Researchers proposed diagnostic criteria for stress cardiomyopathy in 2008.6
- Transient hypokinesis, akinesis or dyskinesis in the LV mid-segments with or without apical involvement. Regional wall motion abnormalities extend beyond a single epicardial vascular 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 (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin.
- Absence of pheochromocytoma and myocarditis.
These modified Mayo criteria are commonly used. Recently, Italian investigators formed a consensus of their own.7 It is indispensable that we reach a worldwide consensus on diagnostic criteria for takotsubo cardiomyopathy.
Patients with takotsubo cardiomyopathy often (>90%) present with chest pain and/or dyspnoea. Despite the absence of obstructive epicardial coronary artery disease, the clinical presentation in patients with the syndrome is similar to that of patients with ST-segment elevation myocardial infarction. The actual cause of this distinctive contractile pattern and the onset mechanism of stress cardiomyopathy are still controversial. Table 1 shows the reported triggers, including both emotional and physical stressors.8
Researchers at the Mayo Clinic prospectively followed 136 patients and reported that 89% of the patients with takotsubo cardiomyopathy had some factors linked to stress.9 Of note, there was a strong predominance of post-menopausal women among the patients with takotsubo cardiomyopathy in the Mayo Clinic cohort: 96% of the patients were female and 90% were over 50 years of age.9 Previous reports combined with our institutional data suggest that this condition accounts for approximately 2% of all patients presenting with apparent acute myocardial infarction.10
Most patients have a rapid increase in cardiac enzyme and biomarker levels. Minimal cardiac enzyme (creatinine kinase and MB isoenzyme of creatinine kinase) increases occur in most cases.11 The concentrations of serum troponin I and/or T and plasma natriuretic peptide also increase in patients with Takotsubo cardiomyopathy. Wittstein et al.4 compared plasma catecholamine concentrations in 13 patients with stress cardiomyopathy and seven subjects hospitalised due to acute myocardial infarction in Killip class III on admission. They found that plasma levels of catecholamine were two to three times higher in patients with transient LV apical ballooning. However, several cases with takotsubo cardiomyopathy did not have elevated catecholamine levels.12 The secretion pattern of brain natriuretic peptide (BNP) in takotsubo patients is quite similar to that in myocardial infarction patients. Low N-terminal prohormone BNP (NT-proBNP) levels on admission were shown to be a reliable parameter indicating a rather favourable prognosis among patients presenting with takotsubo cardiomyopathy.13
The most important finding in patients with takotsubo cardiomyopathy is the existence of ST-elevation or T-wave inversion during the acute and subacute phases of an electrocardiogram. In one report, over 70% of takotsubo cardiomyopathy patients exhibited ST elevation on the electrocardiogram, usually involving the precordial leads.11 The differential diagnosis is important in selecting the appropriate treatment strategy, especially in the acute phase. Various investigators had tried to differentiate between takotsubo cardiomyopathy and acute myocardial infarction using electrocardiograms; however, electrocardiographic findings alone could not reliably distinguish patients with takotsubo cardiomyopathy from those with acute anterior myocardial infarction.14,15 However, based on a recent report of a case of suggestive anterior acute myocardial infarction with ST elevation in the pericordial leads, the presence of ST depression in the aVR lead and the absence of ST elevation in the V1 lead would probably suggest a case of takotsubo cardiomyopathy.16
During the acute phase, all patients had moderate to severe mid-ventricular dysfunction and apical akinesis or diskinesis, with basal function preserved or hyperkinetic. Mid-ventricle and apical wall-motion abnormalities resolved in all surviving patients.4,17 Echocardiography is the most useful first-line examination for the detection of wall-motion abnormalities in patients with takotsubo cardiomyopathy. A dobutamine stress echocardiogram sometimes provokes typical18 and atypical19 takotsubo cardiomyopathy. A 2D echocardiogram using the velocity vector technique for stress cardiomyopathy demonstrated that LV systolic and diastolic dysfunction was observed not only radially but also longitudinally.20 2D21 and 3D22 speckle tracking echocardiograms have now been used in patients with takotsubo cardiomyopathy.
Patients with takotsubo cardiomyopathy have no angiographically detectable coronary disease. Coronary-angiography-suspected takotsubo cardiomyopathy is indispensable to exclude a relevant coronary artery occlusion. The positive ratio of the test for coronary vasospasm in takotsubo patients ranges from 0 to 71.4% (mean 27.6%).11 However, the phenomenon of LV apical ballooning with provocation testing has never appeared.
Left ventriculography is a unique examination for patients with takotsubo cardiomyopathy (see Figure 2). Usually, patients present with LV apical ballooning, as in takotsubo cardiomyopathy, and some cases present with mid-ventricular ballooning or basal and mid-ventricular akinesis with normal apical contractility.23 In cases with typical LV apical ballooning on left ventriculography, the wall-motion abnormality usually extends beyond the distribution of any single coronary artery. Moreover, Swan-Ganz data indicated class III of the Forrester subset.24 Regional wall-motion abnormalities completely resolved in most patients and followed a similar time course to the associated improvement in LV ejection fraction.8,10
From histological analysis obtained from myocardial biopsy specimens, it is known that takotsubo cardiomyopathy is accompanied by severe morphological alterations, with many vacuoles of different sizes contributing to cellular deterioration. Most cases reveal infiltration of mononuclear lymphcytes and macrophages. Interstitial fibrosis, contraction band necrosis and focal myocardial depletion also seemed to be observed.25,26 Apoptotic and autophagic cell death could be excluded by electron microscopy and immunohistochemistry previously described.25
In addition to coronary angiogram findings, coronary microvascular function assessed by myocardial single-photon-emission computed tomography was impaired in patients with takotsubo-like LV dysfunction. The direct evidence for impaired coronary microcirculation is decreased myocardial perfusion without obstructive coronary lesions.
Our previous report using 123I-metaiodobenzilguanidine suggested the existence of cardiac autonomic damage and/or accelerated cardiac sympathetic nervous function in patients with takotsubo cardiomyopathy.27 The mechanism of this neurogenic myocardial stunning may be related to an excess of catecholamines, as seen in takotsubo cardiomyopathy. The recovery of fatty acid metabolism and sympathetic nervous function in the myocardium tends to take much longer than recovery from perfusion insufficiency, especially in the segment presenting the wall-motion abnormality. Investigations using fluorine 18 fluorodeoxyglucose positron-emission tomography were carried out to evaluate the existence of the myocardial metabolic disorder rather than myocardial perfusion in takotsubo cardiomyopathy patients.26 In the acute phase of stress cardiomyopathy, a decrease of the coronary flow reserve in the apical lesion was observed using nitrogen 13 ammonia positronemission tomography,28 as also shown in findings obtained through a coronary angiogram29 and Doppler echocardiogram.30 These findings are helpful in understanding the presence of coronary microcirculation insufficiency.31
Magnetic Resonance Imaging
In contrast to the study using computed tomography with takotsubo cardiomyopathy, which has been rarely cited, the study using cardiac magnetic resonance imaging (MRI) is often described. In order to differentiate patients with takotsubo cardiomyopathy from patients with acute coronary syndrome, cardiac MRI with delayed enhancement is quite useful.32,33 Most cases with takotsubo cardiomyopathy have no delayed contrast enhancement; however, minimal cardiac enzyme release and pathological findings have usually been observed. A recent publication showed that delayed enhancement may well be seen in patients with takotsubo cardiomyopathy due to a remarkable increase in extracellular matrix content.34 Haghi et al.35 have described the importance of right ventricular (RV) function in patients with takotsubo cardiomyopathy. In 26-60% of patients with takotsubo cardiomyopathy present LV apical ballooning accompanying the RV wall-motion abnormalities (biventricular dysfunction).35,36
There are no specific treatments for the LV failure that characterises takotsubo cardiomyopathy, because LV dysfunction is usually normalised within a few weeks. During acute phases, the initial clinical management of patients is similar to that used for acute myocardial infarction. As a supportive treatment, we usually administer a small amount of cardioprotective drugs to patients with takotsubo cardiomyopathy whose condition is absolutely stable, even in cases with New York Heart Association class III. When shock status appears, a mechanical assist device is required to maintain circulatory dynamics.24 If a patient suffers from pulmonary oedema, we use diuretics as an ordinal treatment in patients with congestive heart failure. An angiotensin-converting enzyme inhibitor, angiotensin receptor blocker and/or beta-blocker should be prescribed as routine therapy to patients with LV dysfunction.
However, there have not been any interventional trials observing wall-motion recovery with any drugs, nor any such trials addressing the suitable prescription for patients with stress cardiomyopathy. The administration of a beta-blocker in the acute phase of takotsubo cardiomyopathy is still a matter of debate,9 although the intravenous administration of a beta-blocker is quite useful for stress cardiomyopathy cases complicated by mid-ventricular obstruction.37
Torsades de pointes due to QT prolongation is often observed in patients with takotsubo cardiomyopathy;38 however, the regimen to treat the arrhythmia caused by QT prolongation is not prescribed. The administration of a cardiotonic drug is not deemed suitable because of the underlying stress cardiomyopathy mechanism, as the excess of catecholamine is one of the key elements in the onset of this syndrome.39
Uncertainties remain about anticoagulation in this cardiomyopathy because the formation of intraventricular thrombosis is often observed. Since LV thrombus is more often observed in this cardiomyopathy, heparinisation in the acute phase of takotsubo cardiomyopathy is necessary and indispensable.
The short- and long-term prognosis of takotsubo cardiomyopathy patients is generally favourable. Despite these benign prognoses, there can be fatal complications with this syndrome, such as LV free wall rupture.40 Based on a recent report, the survival ratio in takotsubo patients is significantly decreased compared with the general population.9 Several recurrences were reported recently with the same contractile pattern and with variant form.41 Accurate recurrence rates are difficult to assess as follow-up varies dramatically among series. Only a handful of reports have been published in terms of the recurrence rate of takotsubo cardiomyopathy; the actual ratio was approximately 10%42 or lower.10
Takotsubo cardiomyopathy is a recently recognised, novel entity of acute heart failure that is precipitated by sudden, unexpected emotional distress. Although the underlying mechanisms are too complicated to describe in a few words, clinicians should be aware of the existence and the typical clinical manifestations of this syndrome. This cardiomyopathy should be noted as a possible cause of sudden cardiac death in individuals without obvious heart disease.
Myocardial adrenoceptor hypersensitivity and/or systemic abnormal catecholamine dynamics due to stress may be the primary cause of this cardiomyopathy, and these changes can be attributed to cardiac microvascular impairment. To prevent this syndrome, we should focus on therapeutic and preventative regimens. Further research is needed.
- Sato H, Tateishi H, Uchida T, Takotsubo-type cardiomyopathy due to multivessel spasm. In: Kodama K, Haze K, Hon M (eds), Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure, Tokyo, Japan: Kagakuhyouronsha, 1990;56-64.
- Braunwald E, Kloner RA, The stunned myocardium: prolonged, postischemic ventricular dysfunction, Circulation, 1982;66:1146-9.
- Pavin D, Le Breton H, Daubert C, Human stress cardiomyopathy mimicking acute myocardial syndrome, Heart, 1997;78:509-11.
- Wittstein IS, Thiemann DR, Lima JAC, et al., Neurohumoral features of myocardial stunning due to sudden emotional stress, N Engl J Med, 2005;352:539-48.
- Sharkey SW, Lesser JR, Zenovich AG, et al., Acute and reversible cardiomyopathy provoked by stress in women from the United States, Circulation, 2005;111:472-9.
- Prasad A, Lerman A, Rihal CS, Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction, Am Heart J, 2008;155:408-17.
- Novo S, Akashi Y, Arbustini E, et al., Takotsubo cardiomyopathy: a consensus document, G Ital Cardiol (Rome), 2008;9:785-97.
- Akashi YJ, Nef HM, Mollmann H, Ueyama T, Stress cardiomyopathy, Annu Rev Med, 2010;61:271-86.
- Sharkey SW, Windenburg DC, Lesser JR, et al., Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy, J Am Coll Cardiol, 2010;55:333-41.
- Akashi YJ, Goldstein DS, Barbaro G, Ueyama T, Takotsubo cardiomyopathy: a new form of acute, reversible heart failure, Circulation, 2008;118:2754-62.
- Pilgrim TM, Wyss TR, Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: A systematic review, Int J Cardiol, 2008;124:283-92.
- Morel O, Sauer F, Imperiale A, et al., Importance of inflammation and neurohumoral activation in Takotsubo cardiomyopathy, J Card Fail, 2009;15:206-13.
- Nef HM, Mollmann H, Weber M, et al., Release pattern of cardiac biomarkers in left ventricular apical ballooning, Int J Cardiol, 2007;115:128-9.
- Sharkey SW, Lesser JR, Menon M, et al., Spectrum and significance of electrocardiographic patterns, troponin levels, and thrombolysis in myocardial infarction frame count in patients with stress (tako-tsubo) cardiomyopathy and comparison to those in patients with ST-elevation anterior wall myocardial infarction, Am J Cardiol, 2008;101:1723-8.
- Sharkey SW, Electrocardiogram mimics of acute ST-segment elevation myocardial infarction: insights from cardiac magnetic resonance imaging in patients with tako-tsubo (stress) cardiomyopathy, J Electrocardiol, 2008;41:621-5.
- Kosuge M, Ebina T, Hibi K, et al., Simple and accurate electrocardiographic criteria to differentiate takotsubo cardiomyopathy from anterior acute myocardial infarction, J Am Coll Cardiol, 2010;55:2514-6.
- Haghi D, Papavassiliu T, Fluchter S, et al., Variant form of the acute apical ballooning syndrome (takotsubo cardiomyopathy): observations on a novel entity, Heart, 2006;92:392-4.
- Margey R, Diamond P, McCann H, Sugrue D, Dobutamine stress echo-induced apical ballooning (Takotsubo) syndrome, Eur J Echocardiogr, 2009;10:395-9.
- Cherian J, Kothari S, Angelis D,et al., Atypical takotsubo cardiomyopathy: dobutamine-precipitated apical ballooning with left ventricular outflow tract obstruction, Tex Heart Inst J, 2008;35:73-5.
- Burri MV, Nanda NC, Lloyd SG, et al., Assessment of systolic and diastolic left ventricular and left atrial function using vector velocity imaging in Takotsubo cardiomyopathy, Echocardiography, 2008;25:1138-44.
- Mansencal N, Abbou N, Pilliere R, et al., Usefulness of twodimensional speckle tracking echocardiography for assessment of Tako-Tsubo cardiomyopathy, Am J Cardiol, 2009;103:1020-4.
- Baccouche H, Maunz M, Beck T, et al., Echocardiographic assessment and monitoring of the clinical course in a patient with Tako-Tsubo cardiomyopathy by a novel 3D-speckletracking- strain analysis, Eur J Echocardiogr, 2009;10:729-31.
- Wittstein IS, Acute stress cardiomyopathy, Curr Heart Fail Rep, 2008;5:61-8.
- Akashi YJ, Musha H, Kida K, et al., Reversible ventricular dysfunction takotsubo cardiomyopathy, Eur J Heart Fail, 2005;7:1171-6.
- Nef HM, Mollmann H, Kostin S, et al., Tako-Tsubo cardiomyopathy: intraindividual structural analysis in the acute phase and after functional recovery, Eur Heart J, 2007;28:2456-64.
- Yoshida T, Hibino T, Kako N, et al., A pathophysiologic study of tako-tsubo cardiomyopathy with F-18 fluorodeoxyglucose positron emission tomography, Eur Heart J, 2007;28: 2598-2604.
- Akashi YJ, Nakazawa K, Sakakibara M, et al., 123I-MIBG myocardial scintigraphy in patients with ÔÇ£takotsuboÔÇØ cardiomyopathy, J Nucl Med, 2004;45:1121-7.
- Feola M, Chauvie S, Rosso GL, et al., Reversible impairment of coronary flow reserve in takotsubo cardiomyopathy: a myocardial PET study, J Nucl Cardiol, 2008;15:811-7.
- Kume T, Akasaka T, Kawamoto T, et al., Assessment of coronary microcirculation in patients with takotsubo-like left ventricular dysfunction, Circ J, 2005;69:934-9.
- Meimoun P, Malaquin D, Sayah S, et al., The coronary flow reserve is transiently impaired in tako-tsubo cardiomyopathy: a prospective study using serial Doppler transthoracic echocardiography, J Am Soc Echocardiogr, 2008;21:72-7
- Akashi YJ, Takano M, Miyake F, Scintigraphic imaging in Tako-Tsubo cardiomyopathy, Herz, 2010;35:231-9.
- Nef HM, Mollmann H, Elsasser A, Tako-tsubo cardiomyopathy (apical ballooning), Heart, 2007;93:1309-15.
- Eitel I, Behrendt F, Schindler K, et al., Differential diagnosis of suspected apical ballooning syndrome using contrastenhanced magnetic resonance imaging, Eur Heart J, 2008;29:2651-9.
- Rolf A, Nef HM, Mollmann H, et al., Immunohistological basis of the late gadolinium enhancement phenomenon in takotsubo cardiomyopathy, Eur Heart J, 2009;30:1635-42.
- Haghi D, Athanasiadis A, Papavassiliu T, et al., Right ventricular involvement in Takotsubo cardiomyopathy, Eur Heart J, 2006;27:2433-9.
- Syed IS, Prasad A, Oh JK, et al., Apical ballooning syndrome or aborted acute myocardial infarction? Insights from cardiovascular magnetic resonance imaging, Int J Cardiovasc Imaging, 2008;24:875-82.
- Yoshioka T, Hashimoto A, Tsuchihashi K, et al., Clinical implications of midventricular obstruction and intravenous propranolol use in transient left ventricular apical ballooning (Tako-tsubo cardiomyopathy), Am Heart J, 2008;155:526e1-7.
- Denney SD, Lakkireddy DR, Khan IA, Long QT syndrome and torsade de pointes in transient left ventricular apical ballooning syndrome, Int J Cardiol, 2005;100:499-501.
- Abraham J, Mudd JO, Kapur N, et al., Stress cardiomyopathy after intravenous administration of catecholamines and betareceptor agonists, J Am Coll Cardiol, 2009;53:1320-5.
- Akashi YJ, Tejima T, Sakurada H, et al., Left ventricular rupture associated with Takotsubo cardiomyopathy, Mayo Clin Proc, 2004;79:821-4.
- Izumo M, Akashi YJ, Suzuki K, et al., Recurrent takotsubo cardiomyopathy with variant forms of left ventricular dysfunction, J Cardiol Cases, 2010;2:e37-e40.
- Elesber AA, Prasad A, Lennon RJ, et al., Four-year recurrence rate and prognosis of the apical ballooning syndrome, J Am Coll Cardiol, 2007;50:448-52.