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Heart Online First, published on April 7, 2014 as 10.1136/heartjnl-2013-304691 Education in Heart
MYOCARDIAL DISEASE
Takotsubo cardiomyopathy: still much more to learn Jelena R Ghadri, Frank Ruschitzka, Thomas F Lüscher, Christian Templin ▸ Additional references are published online. To view please visit the journal (http:// dx.doi.org/10.1136/heartjnl2013-304691). University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland Correspondence to Dr Christian Templin, Interventional Cardiology & Acute Cardiac Care, University Heart Center, Department of Cardiology, University Hospital of Zurich, Raemistrasse 100, Zürich CH-8091, Switzerland; [email protected], http://www.takotsubo-registrycom
To cite: Ghadri JR, Ruschitzka F, Lüscher TF, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2013-304691
Takotsubo cardiomyopathy (TTC) was first described in 1990 when Japanese cardiologists from the Hiroshima Asa General Hospital published their findings in a chapter of a Japanese medical text. At that time, TTC was completely unrecognised in Europe and North America, and for years the disorder was thought to affect only Asians. Then in 2003, the first study of TTC in Caucasians indicated that this was actually a widespread affliction.1 By 2013, the number of publications related to TTC had risen to 1879, a number mirroring increased awareness and interest in this disease. But while numerous case reports of TTC exist in the literature, large systematic registries or trials are lacking. The main characteristic of TTC is transient, reversible, systolic dysfunction of the left ventricle. Relatively little definitive information is available otherwise, and as a result many cases likely remain unreported and often misdiagnosed, frequently as acute coronary syndrome (ACS). In particular, TTC may remain unrecognised if symptomatic patients do not undergo corroborating coronary angiography. In this regard, it is likely that subclinical or mild cases of TTC exist, but remain unidentified due to limited diagnostic workup, particularly in centres without primary percutaneous coronary intervention facilities. Not surprisingly, the exact prevalence remains unknown. However, it is estimated that TTC affects approximately 2% of patients presenting as ACS. Rates of TTC in women with ACS are suggested to be higher at 5.9–7.5%.2 3 By searching for the International Classification of Diseases, ninth revision, code 429.83, among 33 506 402 hospitalisations in a nationwide inpatient sample database, Deshmukh et al4 found that 6837 patients in the USA were diagnosed with TTC during 2008, accounting for 0.02% of all hospitalisations that year. Nevertheless, we do not know if cases in the nationwide inpatient sample database were misdiagnosed, wrongly classified, or unrecognised and therefore unreported. Again, a true estimate remains difficult to obtain. The higher prevalence of TTC among women with ACS is not unexpected. Overall, 90% of patients with TTC are women, according to the literature, and these are primarily postmenopausal women.5 6 In the study by Deshmukh et al, women older than 55 years had 4.8 times the risk for TTC when compared with women younger than 55 years—and 10.7 times the risk noted for men of a similar age group.4 Therefore, it is has been suggested that oestrogens might play an important role in this disease. Yet, other factors must be involved in the mechanism, since TTC events have also been
observed in younger premenopausal women and in men. Different hypotheses for the pathophysiology of TTC are currently under consideration. Even the formal nomenclature for TTC—also known as apical ballooning syndrome, broken heart syndrome, or stress induced cardiomyopathy—has yet to be unified. No cardiovascular disease has such a diverse collection of names for the same entity. This phenomenon spurred an article called, “Why not just call it tako-tsubo cardiomyopathy: a discussion of nomenclature”, and as might be expected, vigorous discussion about nomenclature and categorisation continues in the cardiology community.w1 Since 2006, the disease has been labelled as an acquired cardiomyopathy by the American Heart Association.w2 But because the disease mechanism has yet to be explained, the classification of TTC as a cardiomyopathy is certainly worthy of discussion. As the acute presentation is indistinguishable from ACS, TTC could also be classified as a type of ACS. Between 2010 and 2011, we established the International Takotsubo Registry (InterTAKRegistry) at the University Hospital of Zurich. The largest of its kind, the registry includes more than 25 collaborating centres from seven different countries. In collecting a wide range of data, we aim to provide a comprehensive understanding of this complex disease (http://www.takotsubo-registry.com).
CLINICAL PRESENTATION Patients with TTC can present with classic symptoms of angina, and/or they may simply have dyspnoea. Syncope and arrhythmias have also been reported as presenting signs and symptoms; less frequently, patients have been in cardiogenic shock or cardiac arrest on arrival, situations demanding intensive care. Hence, the symptom complex is very similar to ACS, and it cannot be differentiated clinically and by angiography in the acute phase; therefore, TTC has been referred to as a mimic of ACS.7 Contrary to ACS, however, the coronary arteries are typically open and the area of hypokinesia or akinesia of the left ventricle does not match that of any epicardial coronary artery. However, a TTC episode can occur without the typical signs and symptoms. Patients have been discovered incidentally during hospitalisation because of a striking ECG or elevated cardiac enzymes. Most of these patients suffered from severe infection or acute brain injury, or they were postsurgical. Other inpatients have been identified during surgery and anaesthesia. For that reason, heightened awareness of TTC is necessary among disciplines other than cardiology if patients are to be recognised and treated appropriately.
Ghadri JR, etArticle al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691 1 Copyright author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
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Education in Heart In summary, the clinical presentations of TTC can be diverse, with symptoms ranging from nonspecific to life threatening. When symptoms, an abnormal ECG, or elevated cardiac enzymes raise suspicion for TTC, further clinical investigation (echocardiography and coronary angiography) should be undertaken to confirm or exclude TTC.
TRIGGER FACTORS A unique feature of TTC is a preceding emotional or physical trigger. Emotional triggers include anger and sadness—generally, the complicated responses to negative situations, such as financial problems, loss, or bullying. Since the discovery of TTC, a large number of precipitants have been reported, leading to the popular TTC metaphor of ‘broken heart syndrome’. During the last decade, numerous physical stressors have been identified, including hypertensive crisis, surgery, respiratory distress, critical illness, neurologic disease, opiate withdrawal8 or exacerbations of asthma or chronic obstructive pulmonary disease.5 In addition, the use of external catecholamines can elicit a TTC event. However, physical triggers are not yet well appreciated—even among physicians who are aware of TTC. The reported distribution of physical and emotional triggers varies among patient cohorts; while some reports note a predominance of emotional triggers, others have shown that the rate of physical triggers has climbed recently, exceeding that of the emotional triggers.5 Since physical stressors are associated with sicker patients, such as those confined to the intensive care unit, it is conceivable that these patients might have a worse outcome. However, at present, this issue has not been specifically addressed. It is of note that trigger factors can be absent, unidentifiable, or overlapping. We strongly recommend that an in-depth history be obtained. Patients often conceal personal stressors that could be a clue to the correct diagnosis during an emergency admission, so sensitivity while questioning is advised.
significantly between the two patient populations.11 Patients with heart failure had higher troponin values. Yet, in another study, troponin values could not be used to reliably predict the risk for death among patients who had an episode of TTC.12 Similarly, a recent study of 37 patients with TTC revealed that peak troponin I concentrations did not predict acute complications; nor did the ECG results. Instead, physical stress, LV dysfunction, and peak BNP values could predict acute adverse outcomes.13 Another study of 107 patients in a multicentre registry from the Tokyo CCU Network found that a high white blood cell count and an elevated BNP value were both associated with poor clinical outcomes in patients with TTC.w3 Hence, the classic cardiac biomarkers are elevated in TTC, but no specific markers exist for diagnosis. Recently, we identified a signature of four circulating microRNAs that serve as robust biomarkers to distinguish patients with TTC from those with STEMI (figure 1).14 The significant up-regulation of stress and depression related microRNAs suggests a close association of TTC with neuropsychiatric disorders.
TTC TYPES Four different types of TTC have been identified. The most common and classical form, distinguished by LV apical ballooning, was the first one reported and occurs in the majority of cases. Mid-ventricular TTC, the second most observed category, is classified as atypical, as are the rarely reported basal and focal types. Although right ventricular (RV) involvement has been documented, its prevalence is likely underestimated, since echocardiography may not be performed in patients with TTC—or the right ventricle
CARDIAC BIOMARKERS Cardiac enzymes such as troponin, creatine kinase (CK), and creatine kinase-muscle brain (CK-MB) are only mildly elevated in TTC. Cardiac brain natriuretic peptide (BNP) values are often notably increased compared to patients with myocardial infarction.9 A recent study demonstrated up to a threefold increase in patients with TTC compared to ST segment elevation myocardial infarction (STEMI). Peak values are often reached after 24 h, and the subsequent decline can take up to 3 months for complete resolution.10 The high BNP values are an expression of the left ventricular (LV) dysfunction, so typical of TTC. In a population of patients with TTC, those with concomitant acute heart failure were compared against those without acute heart failure; the two groups did not demonstrate a significant difference in BNP values.11 However, concentrations of admission troponin T and peak troponin T varied 2
Figure 1 Receiver operating characteristic curve analysis combining four microRNAs in a signature distinguishing takotsubo cardiomyopathy (TTC) from healthy subjects (74.2% sensitivity, 78.6% specificity) and ST segment elevation acute myocardial infarction (STEMI) (96.8% sensitivity, 70.4% specificity). Figure from Jaguszewski et al14 with copyright permission. Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
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Education in Heart may not have been imaged. In an MRI study, biventricular involvement was shown in 42% of patients, a group that tended to have a worse outcome and longer hospitalisation, than did patients with only LV involvement.15 Overall, isolated RV TTC has been shown to be a very rare condition.w4 Interestingly, patients with recurrent TTC can have different TTC pattern types with repeat episodes. We have recently demonstrated that in one patient with TTC, the position of the ballooning changed during each of the three TTC events.16 Therefore, like theories about the potential contribution of oestrogen to TTC, the hypothesis that sympathetic innervation of particular receptors spurs TTC cannot definitively explain the mechanism.
ELECTROCARDIOGRAPHY With so much variation in the clinical characteristics of patients with TTC, it is probably inevitable that ECG findings also vary among them. Patients can present with ST segment elevation, ST segment depression, T wave inversion, non-specific ECG changes, or even a normal ECG. In most reports, ST segment elevation, mainly in the precordial leads, is documented with the index event, followed, after 1–3 days, by diffuse and often giant T wave inversion and a prolonged QTc interval. Possibly, the relatively high proportion of patients with ST segment elevation indicates selection bias.17 Reciprocal ST segment findings, unusual in TTC, are more commonly seen in ACS.w5 Recently, we have documented transient left axis deviation with precordial R/S transition during the acute stage of TTC.18 This could be due to severe apical ballooning and alterations in the cardiac conduction system.18 It has been suggested that during the prolonged QTc interval, patients are more susceptible to malignant arrhythmia. Migliore et al19 found that the prevalence of life threatening arrhythmia among patients hospitalised for TTC was 8.2%. Predictive ECG findings were giant diffuse negative T waves with pronounced QTc interval prolongation (>500 ms) during the subacute phase. During long term follow-up, it was noted that with normalisation of the QTc interval, no arrhythmia or sudden death occurred in these patients.
INVASIVE AND NON-INVASIVE IMAGING Coronary angiography and echocardiography Coronary angiography with an LV angiogram is the gold standard for excluding ACS and identifying patients with TTC. Therefore, we recommend performing coronary angiography in all patients whose signs and symptoms raise suspicion for TTC. A regional wall motion abnormality might suggest TTC rather than coronary artery stenosis, but it should be noted that the presence of one does not rule out the other. Both coronary artery disease and TTC can be present at the same time. Coronary artery disease frequently exists in older patients with TTC, as most patients are postmenopausal. In this regard, the revised Mayo Clinic diagnostic criteria20 for TTC do not exclude patients with Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
coronary artery disease, and two studies have reported a 10% and 35% occurrence of coronary artery stenosis, defined as 75% and ≥50% occlusion, respectively, among patients with TTC in their study populations.w6 w7 Differentiation between TTC and ACS due to a thrombotic occlusion may also be difficult. However, as mentioned above, TTC wall motion abnormalities (apical, mid-ventricular, basal type) do not match the area of the heart served by either coronary artery, which is obviously different to a thrombotic occlusion. However, differentiation between ACS due to a thrombotic occlusion and the focal TTC type or local myocarditis may be difficult in some cases. In this regard cardiac MRI can be helpful to distinguish between these entities. If TTC is suspected in a patient for whom coronary angiography is contraindicated or unavailable, echocardiography is recommended. Follow-up echocardiography is mandatory in all patients with wall motion abnormalities to confirm full spontaneous recovery. In our experience, echocardiography on the first day after the index event usually shows a gradual improvement of LV function, whereas wall motion abnormalities recover more slowly. Full normalisation of LV function and wall motion abnormalities generally takes approximately 4–8 weeks; however, there are cases in which recovery can take longer.5 Typical echocardiography features found in patients with TTC are: significant reversible mitral regurgitation, LV outflow tract (LVOT) obstruction, systolic anterior motion, RV involvement with reduced function, and apical LV thrombus which can be a complication of severe apical ballooning.
MRI The question of whether or not late gadolinium enhancement (LGE) is found in images from patients with TTC has yet to be fully clarified. While some studies have reported no LGE,w8 w9 others have demonstrated its presence.w10 w11 In the largest MRI study to date, minute focal or patchy non-ischaemic myocardial scarring, as denoted by LGE, was seen in 9% of patients with TTC when a threshold of 3 standard deviations (SDs) above the mean signal intensity for normal myocardium was designated as significant enhancement.15 Yet, at 5 SDs above the mean—the cut-off indicating fibrosis in acute myocardial infarction and myocarditis—none of the patients had evidence of LGE. The authors incorporated their findings into a suggested set of diagnostic criteria for TTC. These were: (1) severe LV dysfunction in a non-coronary regional distribution pattern; (2) myocardial oedema in the same location as the regional wall motion abnormality (oedema should be verified by a quantitative SI analysis, by calculating the signal intensity (SI) ratio between myocardium and skeletal muscle (T2 SI ratio); a cutoff value of 1.9 or more should be used to define oedema); (3) absence of high signal areas in LGE images (a cutoff value of >5 SDs should be used to define significance); and (4) increased early 3
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Education in Heart myocardial gadolinium uptake. The diagnosis is confirmed if after >4 weeks of follow-up, all diagnostic criteria are completely—or almost completely—resolved.15
SPECT and PET In the acute phase of TTC, nuclear cardiac perfusion imaging by single photon emission CT (SPECT) with 99mTc-sestamibi or tetrafosmin shows a perfusion defect with systolic dysfunction; normalisation of perfusion occurs after 1–3 months of
follow-up, as does complete recovery of LV ejection fraction (EF) (figure 2).21–23 In some patients, the recovery period can be shorter. Ito et al demonstrated that even just 3–5 days after the index event, the total defect score was remarkably decreased in comparison to that obtained during the acute event.w12 Cimarelli et al showed no perfusion defect in TTC patients 5–15 days after the index event, although the EF was still impaired.w13 Such findings suggest that the recovery period is variable; more precise data are unlikely to be
Figure 2 A combined perfusion/ metabolism positron emission tomography/CT (PET/CT) study was conducted on the seventh postinterventional day and 3 months later. Perfusion baseline study shows an extensive area of decreased tracer uptake in the apex and mid-ventricular segments without reversibility during stress test and a congruent defect on fluorodeoxyglucose (FDG) PET study. Hyperaemic myocardial blood flow (MBF) and coronary flow reserve (CFR) were globally reduced in the apical, mid-ventricular and basal segments of the left ventricular myocardium. Three months later, full recovery was documented. Figure from Ghadri et al23 with copyright permission.
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Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
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Education in Heart obtained because it would be unethical to subject patients to nuclear imaging every day after an index event due to radiation exposure. Yet, these observations are in line with echocardiographic data that show diverse recovery periods among patients.5 Others have examined the effects of TTC on cardiac perfusion and metabolic activity. Imaging studies using dual isotope myocardial SPECT with 201 thallium and 123I-beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) in patients at rest demonstrated that myocardial fatty acid metabolism was more severely impaired than myocardial perfusion during the early stage of TTC; interestingly, this discrepancy improved steadily during follow-up.w14 Of note, another study found that impaired myocardial fatty acid metabolism was frequently persistent in TTC, even after resolution of LV dysfunction.w15 At 1 month, no difference was observed. However, a major limitation of this retrospective analysis was size, since only 14 patients were studied in the acute phase, and only three were available at follow-up. Other potential limitations were the difference in tissue attenuation between 201thallium and 123 I-BMIPP, and the lack of an established method for downscatter correction. A metabolic perfusion mismatch has also been observed by Obunai et al in five patients who underwent positron emission tomography (PET) perfusion imaging with rubidium-82 and 18F-fluorodeoxyglucose (18F-FDG) for metabolism.w16 A larger study investigating 15 TTC patients showed a reduced 18F-FDG uptake in the apical regions, despite slightly reduced uptake of 201-thallium, which was used as perfusion tracer.w17 The authors suggested a catecholamine induced metabolic disorder as the underlying mechanism of TTC. Microcirculatory disturbances—specifically, reduced myocardial blood flow (MBF) and coronary flow reserve (CFR)—have been seen with PET during the acute phase of TTC.w18 Prasad et al used 11Chydroxyephedrine to examine sympathetic nerve activity in a PET study, and they confirmed abnormal sympathetic activity.w19
PATHOPHYSIOLOGY In 2005, Wittstein et al9 showed for the first time that plasma catecholamines and stress neuropeptides were higher in patients during an acute TTC event than they were in patients with Kilipp class III myocardial infarction. This finding was intriguing and suggested that the hypothalamic–pituitary–adrenal axis played an important role in patients with TTC. Recent studies have confirmed that patients with TTC have elevated catecholamine values.24 w20 In addition, phaeochromocytoma—a catecholamine producing tumour—has been shown to provoke TTC events, as has external application of catecholamines, for example, the use of dobutamine during stress echocardiography. These findings further support the concept of a catecholamine mediated vasoconstriction of the microcirculation in TTC. This hypothesis is also substantiated by myocardial scintigraphy demonstrating an increased washout rate of 123I-metaiodobenzyl guanidine (123I-MIBG) Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
—evidence of sympathetic nervous system overactivity—in patients with TTC. Precisely how catecholamines affect the heart is still unclear, however, histologic, evidence of their influence has been found in biopsy specimens from hearts marked by contraction band necrosis. The disorder, characterised by hypercontraction of sarcomeres, dense eosinophilic transverse bands, and mononuclear cell infiltration, has been attributed to catecholamine excess. In one study, high dose epinephrine, but not norepinephrine, led to TTC in a rat model.25 The researchers proposed that epinephrine activated a switch of β2-adrenergic receptor coupling from the positively inotropic Gs-cAMP to a negatively inotropic Gi signalling pathway. If epinephrine-G(i) effects were inhibited, the mortality rate was increased in the TTC model. While β-blockers ( propranolol, carvedilol) that activated β2AR-G(i) exacerbated the epinephrine dependent negative inotropic effects without additional deaths, bisoprolol showed no effect.25 Furthermore, the application of levosimendan, a calcium channel sensitiser, completely resolved the acute TTC episode, with 100% survival. Nonetheless, the study results only pertain to the apical ballooning form of TTC—they do not explain the other TTC types. Secondly, studies in humans have not shown a 100% survival when levosimendan was applied. Thirdly, elevated catecholamine concentrations have not been found in all study participants with TTC.w21–w23 Epicardial spasm has also been proposed as an underlying mechanism for TTC. However, this hypothesis has not been confirmed, and vasospasm has only been noted in case reports of individual patients. Furthermore, provocative substances, such as acetylcholine or ergonovine, have failed to induce a recurrent TTC pattern.w24 During these provocative tests, no typical ECG changes have been observed and treatment with calcium antagonists and nitrates has not been effective in ameliorating acute TTC. Of note, epicardial spasm does not explain each of the different wall motion abnormalities documented in TTC. Therefore, we have several compelling reasons to doubt this hypothesis. Results from imaging studies employing PET, Doppler transthoracic echocardiography, or coronary angiography indicate that coronary microcirculatory impairment could be a potential mechanism in TTC. For example, a substantial decrease in CFR and velocity has been reported during coronary angiography with a Doppler flow guide wire.w25 In another study, 10 patients with a previous diagnosis of TTC underwent coronary vasomotion testing and were found to have chronically impaired coronary vascular reactivity, which indicates microcirculatory dysfunction.w26 Echocardiography has revealed that an infusion of adenosine can temporarily reverse microvascular dysfunction during the acute phase of TTC, leading to an improvement in myocardial function.26 Therefore, coronary microvascular vasoconstriction could represent a comprehensive pathophysiological mechanism. 5
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Education in Heart Moreover, an impaired CFR has been documented by cardiac PET studies. We have recently shown that CFR and MBF were not solely restricted to the dysfunctional LV myocardium but, in fact, were globally impaired. This finding led us to conclude that microcirculatory dysfunction is a general phenomenon in TTC, though it is more severe in regions with contractile dysfunction. However, whether this contributes to the pathophysiology or is a secondary cause of TTC remains to be determined. We postulate that TTC is a multifactorial disease in which a number of elements increase a patient’s vulnerability so that, ultimately, a critical threshold is reached and an intricate cascade of biochemical events is triggered, causing a TTC event. There are compelling reasons to assume that these susceptibility traits comprise neurologic and psychiatric disease, hormonal changes, age, female gender, genetics, and stressful life events (figure 3).
DIAGNOSTIC CRITERIA In 2004, Prasad et al from the Mayo Clinic were the first to establish diagnostic criteria for TTC.7 Then in 2008, the same group incorporated increased knowledge about the disease into a revision of the original criteria.20 Meanwhile the Japanese,w22 Gothenburg,w27 and Johns Hopkins diagnostic criteriaw28 were also introduced. Only the Japanese criteria were based on a nationwide consensus; the rest were limited by data from single centre or own experience. At the same time, the Japanese centres were all located in Japan, raising questions about the generalisability of their results. While all of these sets of criteria have overlapping advantages and disadvantages, a global consensus has been lacking to date. Acknowledged limitations of the available criteria include exclusion of
Figure 3 A critical threshold needs to be reached to initiate a cascade of biochemical events causing a takotsubo cardiomyopathy (TTC) event. The susceptibility traits comprise neurologic and psychiatric disease, hormonal changes, age, female gender, genetics, and stressful life events. SAH, subarachnoid haemorrhage. 6
Box 1 Different cardiovascular complications that can occur during an acute takotsubo event ▸ ▸ ▸ ▸ ▸ ▸ ▸ ▸
Heart failure Ventricular thrombus Cardiogenic shock Life threatening arrhythmia Left ventricular outflow tract obstruction Mitral regurgitation Ventricular rupture Death
patients whose recovery was not confirmed; patients with phaeochromocytoma, which causes catecholamine spillover; and patients with neurogenic mediated diseases. The latter two diagnoses share common characteristics with TTC and therefore should not be excluded in our view. Obstructive coronary artery disease should not exclude TTC, as the diseases can occur concomitantly. Considering these limitations, the true prevalence of TTC, as noted earlier, is likely to be underreported.
PROGNOSIS AND TREATMENT Several complications (box 1) can occur in TTC, including heart failure, arrhythmia, cardiogenic shock, LVOT obstruction, mitral regurgitation, ventricular thrombus, cardiac rupture27 (figure 4), and death. While many studies report a good long term prognosis, the acute phase of TTC can truly be life threatening. Mortality rates of up to 2% have been reported.w29 For patients who overcome the acute phase, the long term prognosis has been shown to be good, with LV recovery occurring within 4–8 weeks. However, Sharkey et al have demonstrated that in 5% of cases, normalisation of EF can take 2.5–12 months. Therefore, serial echocardiography is mandatory to document normalisation. Two large studies have analysed long term prognosis. In one (n=100), long term survival for those discharged from hospital was similar to that of an age and gender matched population; a recurrence rate of 11.4% was noted.12 In another, the risk for all-cause mortality was greater among patients who had suffered a TTC event when compared to an age and gender matched population.5 Risk of death was greatest in the year following diagnosis of TTC and then dropped considerably in the ensuing years. These deaths were not due to cardiac causes, however, and included nine patients with cancer, four of whom had experienced a TTC episode associated with the disease. Yet in this study the recurrence rate was lower at 5%.5 Further studies are needed to clarify the conflicting results. There are no randomised controlled trials on the treatment of TTC. Treatment strategies are therefore based on clinical judgment only and can be divided into acute and chronic therapy (table 1). Since ACS remains an important part of the Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
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Education in Heart
Figure 4 Autopsy shows a wide penetrating apical rupture in a patient with takotsubo cardiomyopathy. Figure from Jaguszewski et al27 with copyright permission.
differential diagnosis when patients with TTC arrive in the emergency room, treatment of ACS should not be delayed. Aspirin and heparin can be administered initially. If cardiogenic shock—with or without ventricular outflow tract obstruction—is present in the acute phase, an intra-aortic balloon pump can be inserted to support the haemodynamic state. In our experience, this strategy has provided a good outcome. The use of catecholamines as inotropic agents should be considered carefully, since this disease is thought to be
Table 1 Acute in-hospital treatment and discharge medication in takotsubo cardiomyopathy Acute treatment
Treatment at discharge
β-blockers ▸ Choose one with β-blocking and α-adrenergic receptor blocking properties—not in decompensated patients Diuretics ▸ For volume overload (pulmonary oedema, LVEDP↑) IABP ▸ In cardiogenic shock
β-blockers ▸ Prevent recurrence?
Inotropics ▸ Levosimendan (combined inotropic and vasodilatory action) ▸ Dobutamine or norepinephrine can worsen LVOT obstruction Avoid: QT prolonging drugs Novel drug that need to be tested: ▸ relaxine?
ACE inhibitors or ARBs ▸ In patients with reduced LV function until recovery Anticoagulation ▸ If LV thrombus is present or if severe apical ballooning exists to prevent thrombus formation ASA+statins ▸ If coronary atherosclerosis is present
Antidepressants ▸ Considered in depression and anxiety Novel drugs that need to be tested: ▸ Oestrogen supplementation: to prevent recurrence?
ACE, angiotensin converting enzyme; ASA, acetylsalicylic acid; ARBs, angiotensin receptor blockers; IABP, intra-aortic balloon pump; LVEDP, left ventricular end diastolic pressure; LVOT, left ventricular outflow tract.
Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
catecholamine mediated, and outflow tract obstruction can be worsened. An alternative in many countries is the calcium channel sensitiser levosimendan, which is not currently marketed in the USA. A recent prospective study in 13 patients with TTC and low EF (
Heart Online First, published on April 7, 2014 as 10.1136/heartjnl-2013-304691 Education in Heart
MYOCARDIAL DISEASE
Takotsubo cardiomyopathy: still much more to learn Jelena R Ghadri, Frank Ruschitzka, Thomas F Lüscher, Christian Templin ▸ Additional references are published online. To view please visit the journal (http:// dx.doi.org/10.1136/heartjnl2013-304691). University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland Correspondence to Dr Christian Templin, Interventional Cardiology & Acute Cardiac Care, University Heart Center, Department of Cardiology, University Hospital of Zurich, Raemistrasse 100, Zürich CH-8091, Switzerland; [email protected], http://www.takotsubo-registrycom
To cite: Ghadri JR, Ruschitzka F, Lüscher TF, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2013-304691
Takotsubo cardiomyopathy (TTC) was first described in 1990 when Japanese cardiologists from the Hiroshima Asa General Hospital published their findings in a chapter of a Japanese medical text. At that time, TTC was completely unrecognised in Europe and North America, and for years the disorder was thought to affect only Asians. Then in 2003, the first study of TTC in Caucasians indicated that this was actually a widespread affliction.1 By 2013, the number of publications related to TTC had risen to 1879, a number mirroring increased awareness and interest in this disease. But while numerous case reports of TTC exist in the literature, large systematic registries or trials are lacking. The main characteristic of TTC is transient, reversible, systolic dysfunction of the left ventricle. Relatively little definitive information is available otherwise, and as a result many cases likely remain unreported and often misdiagnosed, frequently as acute coronary syndrome (ACS). In particular, TTC may remain unrecognised if symptomatic patients do not undergo corroborating coronary angiography. In this regard, it is likely that subclinical or mild cases of TTC exist, but remain unidentified due to limited diagnostic workup, particularly in centres without primary percutaneous coronary intervention facilities. Not surprisingly, the exact prevalence remains unknown. However, it is estimated that TTC affects approximately 2% of patients presenting as ACS. Rates of TTC in women with ACS are suggested to be higher at 5.9–7.5%.2 3 By searching for the International Classification of Diseases, ninth revision, code 429.83, among 33 506 402 hospitalisations in a nationwide inpatient sample database, Deshmukh et al4 found that 6837 patients in the USA were diagnosed with TTC during 2008, accounting for 0.02% of all hospitalisations that year. Nevertheless, we do not know if cases in the nationwide inpatient sample database were misdiagnosed, wrongly classified, or unrecognised and therefore unreported. Again, a true estimate remains difficult to obtain. The higher prevalence of TTC among women with ACS is not unexpected. Overall, 90% of patients with TTC are women, according to the literature, and these are primarily postmenopausal women.5 6 In the study by Deshmukh et al, women older than 55 years had 4.8 times the risk for TTC when compared with women younger than 55 years—and 10.7 times the risk noted for men of a similar age group.4 Therefore, it is has been suggested that oestrogens might play an important role in this disease. Yet, other factors must be involved in the mechanism, since TTC events have also been
observed in younger premenopausal women and in men. Different hypotheses for the pathophysiology of TTC are currently under consideration. Even the formal nomenclature for TTC—also known as apical ballooning syndrome, broken heart syndrome, or stress induced cardiomyopathy—has yet to be unified. No cardiovascular disease has such a diverse collection of names for the same entity. This phenomenon spurred an article called, “Why not just call it tako-tsubo cardiomyopathy: a discussion of nomenclature”, and as might be expected, vigorous discussion about nomenclature and categorisation continues in the cardiology community.w1 Since 2006, the disease has been labelled as an acquired cardiomyopathy by the American Heart Association.w2 But because the disease mechanism has yet to be explained, the classification of TTC as a cardiomyopathy is certainly worthy of discussion. As the acute presentation is indistinguishable from ACS, TTC could also be classified as a type of ACS. Between 2010 and 2011, we established the International Takotsubo Registry (InterTAKRegistry) at the University Hospital of Zurich. The largest of its kind, the registry includes more than 25 collaborating centres from seven different countries. In collecting a wide range of data, we aim to provide a comprehensive understanding of this complex disease (http://www.takotsubo-registry.com).
CLINICAL PRESENTATION Patients with TTC can present with classic symptoms of angina, and/or they may simply have dyspnoea. Syncope and arrhythmias have also been reported as presenting signs and symptoms; less frequently, patients have been in cardiogenic shock or cardiac arrest on arrival, situations demanding intensive care. Hence, the symptom complex is very similar to ACS, and it cannot be differentiated clinically and by angiography in the acute phase; therefore, TTC has been referred to as a mimic of ACS.7 Contrary to ACS, however, the coronary arteries are typically open and the area of hypokinesia or akinesia of the left ventricle does not match that of any epicardial coronary artery. However, a TTC episode can occur without the typical signs and symptoms. Patients have been discovered incidentally during hospitalisation because of a striking ECG or elevated cardiac enzymes. Most of these patients suffered from severe infection or acute brain injury, or they were postsurgical. Other inpatients have been identified during surgery and anaesthesia. For that reason, heightened awareness of TTC is necessary among disciplines other than cardiology if patients are to be recognised and treated appropriately.
Ghadri JR, etArticle al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691 1 Copyright author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
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Education in Heart In summary, the clinical presentations of TTC can be diverse, with symptoms ranging from nonspecific to life threatening. When symptoms, an abnormal ECG, or elevated cardiac enzymes raise suspicion for TTC, further clinical investigation (echocardiography and coronary angiography) should be undertaken to confirm or exclude TTC.
TRIGGER FACTORS A unique feature of TTC is a preceding emotional or physical trigger. Emotional triggers include anger and sadness—generally, the complicated responses to negative situations, such as financial problems, loss, or bullying. Since the discovery of TTC, a large number of precipitants have been reported, leading to the popular TTC metaphor of ‘broken heart syndrome’. During the last decade, numerous physical stressors have been identified, including hypertensive crisis, surgery, respiratory distress, critical illness, neurologic disease, opiate withdrawal8 or exacerbations of asthma or chronic obstructive pulmonary disease.5 In addition, the use of external catecholamines can elicit a TTC event. However, physical triggers are not yet well appreciated—even among physicians who are aware of TTC. The reported distribution of physical and emotional triggers varies among patient cohorts; while some reports note a predominance of emotional triggers, others have shown that the rate of physical triggers has climbed recently, exceeding that of the emotional triggers.5 Since physical stressors are associated with sicker patients, such as those confined to the intensive care unit, it is conceivable that these patients might have a worse outcome. However, at present, this issue has not been specifically addressed. It is of note that trigger factors can be absent, unidentifiable, or overlapping. We strongly recommend that an in-depth history be obtained. Patients often conceal personal stressors that could be a clue to the correct diagnosis during an emergency admission, so sensitivity while questioning is advised.
significantly between the two patient populations.11 Patients with heart failure had higher troponin values. Yet, in another study, troponin values could not be used to reliably predict the risk for death among patients who had an episode of TTC.12 Similarly, a recent study of 37 patients with TTC revealed that peak troponin I concentrations did not predict acute complications; nor did the ECG results. Instead, physical stress, LV dysfunction, and peak BNP values could predict acute adverse outcomes.13 Another study of 107 patients in a multicentre registry from the Tokyo CCU Network found that a high white blood cell count and an elevated BNP value were both associated with poor clinical outcomes in patients with TTC.w3 Hence, the classic cardiac biomarkers are elevated in TTC, but no specific markers exist for diagnosis. Recently, we identified a signature of four circulating microRNAs that serve as robust biomarkers to distinguish patients with TTC from those with STEMI (figure 1).14 The significant up-regulation of stress and depression related microRNAs suggests a close association of TTC with neuropsychiatric disorders.
TTC TYPES Four different types of TTC have been identified. The most common and classical form, distinguished by LV apical ballooning, was the first one reported and occurs in the majority of cases. Mid-ventricular TTC, the second most observed category, is classified as atypical, as are the rarely reported basal and focal types. Although right ventricular (RV) involvement has been documented, its prevalence is likely underestimated, since echocardiography may not be performed in patients with TTC—or the right ventricle
CARDIAC BIOMARKERS Cardiac enzymes such as troponin, creatine kinase (CK), and creatine kinase-muscle brain (CK-MB) are only mildly elevated in TTC. Cardiac brain natriuretic peptide (BNP) values are often notably increased compared to patients with myocardial infarction.9 A recent study demonstrated up to a threefold increase in patients with TTC compared to ST segment elevation myocardial infarction (STEMI). Peak values are often reached after 24 h, and the subsequent decline can take up to 3 months for complete resolution.10 The high BNP values are an expression of the left ventricular (LV) dysfunction, so typical of TTC. In a population of patients with TTC, those with concomitant acute heart failure were compared against those without acute heart failure; the two groups did not demonstrate a significant difference in BNP values.11 However, concentrations of admission troponin T and peak troponin T varied 2
Figure 1 Receiver operating characteristic curve analysis combining four microRNAs in a signature distinguishing takotsubo cardiomyopathy (TTC) from healthy subjects (74.2% sensitivity, 78.6% specificity) and ST segment elevation acute myocardial infarction (STEMI) (96.8% sensitivity, 70.4% specificity). Figure from Jaguszewski et al14 with copyright permission. Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
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Education in Heart may not have been imaged. In an MRI study, biventricular involvement was shown in 42% of patients, a group that tended to have a worse outcome and longer hospitalisation, than did patients with only LV involvement.15 Overall, isolated RV TTC has been shown to be a very rare condition.w4 Interestingly, patients with recurrent TTC can have different TTC pattern types with repeat episodes. We have recently demonstrated that in one patient with TTC, the position of the ballooning changed during each of the three TTC events.16 Therefore, like theories about the potential contribution of oestrogen to TTC, the hypothesis that sympathetic innervation of particular receptors spurs TTC cannot definitively explain the mechanism.
ELECTROCARDIOGRAPHY With so much variation in the clinical characteristics of patients with TTC, it is probably inevitable that ECG findings also vary among them. Patients can present with ST segment elevation, ST segment depression, T wave inversion, non-specific ECG changes, or even a normal ECG. In most reports, ST segment elevation, mainly in the precordial leads, is documented with the index event, followed, after 1–3 days, by diffuse and often giant T wave inversion and a prolonged QTc interval. Possibly, the relatively high proportion of patients with ST segment elevation indicates selection bias.17 Reciprocal ST segment findings, unusual in TTC, are more commonly seen in ACS.w5 Recently, we have documented transient left axis deviation with precordial R/S transition during the acute stage of TTC.18 This could be due to severe apical ballooning and alterations in the cardiac conduction system.18 It has been suggested that during the prolonged QTc interval, patients are more susceptible to malignant arrhythmia. Migliore et al19 found that the prevalence of life threatening arrhythmia among patients hospitalised for TTC was 8.2%. Predictive ECG findings were giant diffuse negative T waves with pronounced QTc interval prolongation (>500 ms) during the subacute phase. During long term follow-up, it was noted that with normalisation of the QTc interval, no arrhythmia or sudden death occurred in these patients.
INVASIVE AND NON-INVASIVE IMAGING Coronary angiography and echocardiography Coronary angiography with an LV angiogram is the gold standard for excluding ACS and identifying patients with TTC. Therefore, we recommend performing coronary angiography in all patients whose signs and symptoms raise suspicion for TTC. A regional wall motion abnormality might suggest TTC rather than coronary artery stenosis, but it should be noted that the presence of one does not rule out the other. Both coronary artery disease and TTC can be present at the same time. Coronary artery disease frequently exists in older patients with TTC, as most patients are postmenopausal. In this regard, the revised Mayo Clinic diagnostic criteria20 for TTC do not exclude patients with Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
coronary artery disease, and two studies have reported a 10% and 35% occurrence of coronary artery stenosis, defined as 75% and ≥50% occlusion, respectively, among patients with TTC in their study populations.w6 w7 Differentiation between TTC and ACS due to a thrombotic occlusion may also be difficult. However, as mentioned above, TTC wall motion abnormalities (apical, mid-ventricular, basal type) do not match the area of the heart served by either coronary artery, which is obviously different to a thrombotic occlusion. However, differentiation between ACS due to a thrombotic occlusion and the focal TTC type or local myocarditis may be difficult in some cases. In this regard cardiac MRI can be helpful to distinguish between these entities. If TTC is suspected in a patient for whom coronary angiography is contraindicated or unavailable, echocardiography is recommended. Follow-up echocardiography is mandatory in all patients with wall motion abnormalities to confirm full spontaneous recovery. In our experience, echocardiography on the first day after the index event usually shows a gradual improvement of LV function, whereas wall motion abnormalities recover more slowly. Full normalisation of LV function and wall motion abnormalities generally takes approximately 4–8 weeks; however, there are cases in which recovery can take longer.5 Typical echocardiography features found in patients with TTC are: significant reversible mitral regurgitation, LV outflow tract (LVOT) obstruction, systolic anterior motion, RV involvement with reduced function, and apical LV thrombus which can be a complication of severe apical ballooning.
MRI The question of whether or not late gadolinium enhancement (LGE) is found in images from patients with TTC has yet to be fully clarified. While some studies have reported no LGE,w8 w9 others have demonstrated its presence.w10 w11 In the largest MRI study to date, minute focal or patchy non-ischaemic myocardial scarring, as denoted by LGE, was seen in 9% of patients with TTC when a threshold of 3 standard deviations (SDs) above the mean signal intensity for normal myocardium was designated as significant enhancement.15 Yet, at 5 SDs above the mean—the cut-off indicating fibrosis in acute myocardial infarction and myocarditis—none of the patients had evidence of LGE. The authors incorporated their findings into a suggested set of diagnostic criteria for TTC. These were: (1) severe LV dysfunction in a non-coronary regional distribution pattern; (2) myocardial oedema in the same location as the regional wall motion abnormality (oedema should be verified by a quantitative SI analysis, by calculating the signal intensity (SI) ratio between myocardium and skeletal muscle (T2 SI ratio); a cutoff value of 1.9 or more should be used to define oedema); (3) absence of high signal areas in LGE images (a cutoff value of >5 SDs should be used to define significance); and (4) increased early 3
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Education in Heart myocardial gadolinium uptake. The diagnosis is confirmed if after >4 weeks of follow-up, all diagnostic criteria are completely—or almost completely—resolved.15
SPECT and PET In the acute phase of TTC, nuclear cardiac perfusion imaging by single photon emission CT (SPECT) with 99mTc-sestamibi or tetrafosmin shows a perfusion defect with systolic dysfunction; normalisation of perfusion occurs after 1–3 months of
follow-up, as does complete recovery of LV ejection fraction (EF) (figure 2).21–23 In some patients, the recovery period can be shorter. Ito et al demonstrated that even just 3–5 days after the index event, the total defect score was remarkably decreased in comparison to that obtained during the acute event.w12 Cimarelli et al showed no perfusion defect in TTC patients 5–15 days after the index event, although the EF was still impaired.w13 Such findings suggest that the recovery period is variable; more precise data are unlikely to be
Figure 2 A combined perfusion/ metabolism positron emission tomography/CT (PET/CT) study was conducted on the seventh postinterventional day and 3 months later. Perfusion baseline study shows an extensive area of decreased tracer uptake in the apex and mid-ventricular segments without reversibility during stress test and a congruent defect on fluorodeoxyglucose (FDG) PET study. Hyperaemic myocardial blood flow (MBF) and coronary flow reserve (CFR) were globally reduced in the apical, mid-ventricular and basal segments of the left ventricular myocardium. Three months later, full recovery was documented. Figure from Ghadri et al23 with copyright permission.
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Education in Heart obtained because it would be unethical to subject patients to nuclear imaging every day after an index event due to radiation exposure. Yet, these observations are in line with echocardiographic data that show diverse recovery periods among patients.5 Others have examined the effects of TTC on cardiac perfusion and metabolic activity. Imaging studies using dual isotope myocardial SPECT with 201 thallium and 123I-beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) in patients at rest demonstrated that myocardial fatty acid metabolism was more severely impaired than myocardial perfusion during the early stage of TTC; interestingly, this discrepancy improved steadily during follow-up.w14 Of note, another study found that impaired myocardial fatty acid metabolism was frequently persistent in TTC, even after resolution of LV dysfunction.w15 At 1 month, no difference was observed. However, a major limitation of this retrospective analysis was size, since only 14 patients were studied in the acute phase, and only three were available at follow-up. Other potential limitations were the difference in tissue attenuation between 201thallium and 123 I-BMIPP, and the lack of an established method for downscatter correction. A metabolic perfusion mismatch has also been observed by Obunai et al in five patients who underwent positron emission tomography (PET) perfusion imaging with rubidium-82 and 18F-fluorodeoxyglucose (18F-FDG) for metabolism.w16 A larger study investigating 15 TTC patients showed a reduced 18F-FDG uptake in the apical regions, despite slightly reduced uptake of 201-thallium, which was used as perfusion tracer.w17 The authors suggested a catecholamine induced metabolic disorder as the underlying mechanism of TTC. Microcirculatory disturbances—specifically, reduced myocardial blood flow (MBF) and coronary flow reserve (CFR)—have been seen with PET during the acute phase of TTC.w18 Prasad et al used 11Chydroxyephedrine to examine sympathetic nerve activity in a PET study, and they confirmed abnormal sympathetic activity.w19
PATHOPHYSIOLOGY In 2005, Wittstein et al9 showed for the first time that plasma catecholamines and stress neuropeptides were higher in patients during an acute TTC event than they were in patients with Kilipp class III myocardial infarction. This finding was intriguing and suggested that the hypothalamic–pituitary–adrenal axis played an important role in patients with TTC. Recent studies have confirmed that patients with TTC have elevated catecholamine values.24 w20 In addition, phaeochromocytoma—a catecholamine producing tumour—has been shown to provoke TTC events, as has external application of catecholamines, for example, the use of dobutamine during stress echocardiography. These findings further support the concept of a catecholamine mediated vasoconstriction of the microcirculation in TTC. This hypothesis is also substantiated by myocardial scintigraphy demonstrating an increased washout rate of 123I-metaiodobenzyl guanidine (123I-MIBG) Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
—evidence of sympathetic nervous system overactivity—in patients with TTC. Precisely how catecholamines affect the heart is still unclear, however, histologic, evidence of their influence has been found in biopsy specimens from hearts marked by contraction band necrosis. The disorder, characterised by hypercontraction of sarcomeres, dense eosinophilic transverse bands, and mononuclear cell infiltration, has been attributed to catecholamine excess. In one study, high dose epinephrine, but not norepinephrine, led to TTC in a rat model.25 The researchers proposed that epinephrine activated a switch of β2-adrenergic receptor coupling from the positively inotropic Gs-cAMP to a negatively inotropic Gi signalling pathway. If epinephrine-G(i) effects were inhibited, the mortality rate was increased in the TTC model. While β-blockers ( propranolol, carvedilol) that activated β2AR-G(i) exacerbated the epinephrine dependent negative inotropic effects without additional deaths, bisoprolol showed no effect.25 Furthermore, the application of levosimendan, a calcium channel sensitiser, completely resolved the acute TTC episode, with 100% survival. Nonetheless, the study results only pertain to the apical ballooning form of TTC—they do not explain the other TTC types. Secondly, studies in humans have not shown a 100% survival when levosimendan was applied. Thirdly, elevated catecholamine concentrations have not been found in all study participants with TTC.w21–w23 Epicardial spasm has also been proposed as an underlying mechanism for TTC. However, this hypothesis has not been confirmed, and vasospasm has only been noted in case reports of individual patients. Furthermore, provocative substances, such as acetylcholine or ergonovine, have failed to induce a recurrent TTC pattern.w24 During these provocative tests, no typical ECG changes have been observed and treatment with calcium antagonists and nitrates has not been effective in ameliorating acute TTC. Of note, epicardial spasm does not explain each of the different wall motion abnormalities documented in TTC. Therefore, we have several compelling reasons to doubt this hypothesis. Results from imaging studies employing PET, Doppler transthoracic echocardiography, or coronary angiography indicate that coronary microcirculatory impairment could be a potential mechanism in TTC. For example, a substantial decrease in CFR and velocity has been reported during coronary angiography with a Doppler flow guide wire.w25 In another study, 10 patients with a previous diagnosis of TTC underwent coronary vasomotion testing and were found to have chronically impaired coronary vascular reactivity, which indicates microcirculatory dysfunction.w26 Echocardiography has revealed that an infusion of adenosine can temporarily reverse microvascular dysfunction during the acute phase of TTC, leading to an improvement in myocardial function.26 Therefore, coronary microvascular vasoconstriction could represent a comprehensive pathophysiological mechanism. 5
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Education in Heart Moreover, an impaired CFR has been documented by cardiac PET studies. We have recently shown that CFR and MBF were not solely restricted to the dysfunctional LV myocardium but, in fact, were globally impaired. This finding led us to conclude that microcirculatory dysfunction is a general phenomenon in TTC, though it is more severe in regions with contractile dysfunction. However, whether this contributes to the pathophysiology or is a secondary cause of TTC remains to be determined. We postulate that TTC is a multifactorial disease in which a number of elements increase a patient’s vulnerability so that, ultimately, a critical threshold is reached and an intricate cascade of biochemical events is triggered, causing a TTC event. There are compelling reasons to assume that these susceptibility traits comprise neurologic and psychiatric disease, hormonal changes, age, female gender, genetics, and stressful life events (figure 3).
DIAGNOSTIC CRITERIA In 2004, Prasad et al from the Mayo Clinic were the first to establish diagnostic criteria for TTC.7 Then in 2008, the same group incorporated increased knowledge about the disease into a revision of the original criteria.20 Meanwhile the Japanese,w22 Gothenburg,w27 and Johns Hopkins diagnostic criteriaw28 were also introduced. Only the Japanese criteria were based on a nationwide consensus; the rest were limited by data from single centre or own experience. At the same time, the Japanese centres were all located in Japan, raising questions about the generalisability of their results. While all of these sets of criteria have overlapping advantages and disadvantages, a global consensus has been lacking to date. Acknowledged limitations of the available criteria include exclusion of
Figure 3 A critical threshold needs to be reached to initiate a cascade of biochemical events causing a takotsubo cardiomyopathy (TTC) event. The susceptibility traits comprise neurologic and psychiatric disease, hormonal changes, age, female gender, genetics, and stressful life events. SAH, subarachnoid haemorrhage. 6
Box 1 Different cardiovascular complications that can occur during an acute takotsubo event ▸ ▸ ▸ ▸ ▸ ▸ ▸ ▸
Heart failure Ventricular thrombus Cardiogenic shock Life threatening arrhythmia Left ventricular outflow tract obstruction Mitral regurgitation Ventricular rupture Death
patients whose recovery was not confirmed; patients with phaeochromocytoma, which causes catecholamine spillover; and patients with neurogenic mediated diseases. The latter two diagnoses share common characteristics with TTC and therefore should not be excluded in our view. Obstructive coronary artery disease should not exclude TTC, as the diseases can occur concomitantly. Considering these limitations, the true prevalence of TTC, as noted earlier, is likely to be underreported.
PROGNOSIS AND TREATMENT Several complications (box 1) can occur in TTC, including heart failure, arrhythmia, cardiogenic shock, LVOT obstruction, mitral regurgitation, ventricular thrombus, cardiac rupture27 (figure 4), and death. While many studies report a good long term prognosis, the acute phase of TTC can truly be life threatening. Mortality rates of up to 2% have been reported.w29 For patients who overcome the acute phase, the long term prognosis has been shown to be good, with LV recovery occurring within 4–8 weeks. However, Sharkey et al have demonstrated that in 5% of cases, normalisation of EF can take 2.5–12 months. Therefore, serial echocardiography is mandatory to document normalisation. Two large studies have analysed long term prognosis. In one (n=100), long term survival for those discharged from hospital was similar to that of an age and gender matched population; a recurrence rate of 11.4% was noted.12 In another, the risk for all-cause mortality was greater among patients who had suffered a TTC event when compared to an age and gender matched population.5 Risk of death was greatest in the year following diagnosis of TTC and then dropped considerably in the ensuing years. These deaths were not due to cardiac causes, however, and included nine patients with cancer, four of whom had experienced a TTC episode associated with the disease. Yet in this study the recurrence rate was lower at 5%.5 Further studies are needed to clarify the conflicting results. There are no randomised controlled trials on the treatment of TTC. Treatment strategies are therefore based on clinical judgment only and can be divided into acute and chronic therapy (table 1). Since ACS remains an important part of the Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
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Education in Heart
Figure 4 Autopsy shows a wide penetrating apical rupture in a patient with takotsubo cardiomyopathy. Figure from Jaguszewski et al27 with copyright permission.
differential diagnosis when patients with TTC arrive in the emergency room, treatment of ACS should not be delayed. Aspirin and heparin can be administered initially. If cardiogenic shock—with or without ventricular outflow tract obstruction—is present in the acute phase, an intra-aortic balloon pump can be inserted to support the haemodynamic state. In our experience, this strategy has provided a good outcome. The use of catecholamines as inotropic agents should be considered carefully, since this disease is thought to be
Table 1 Acute in-hospital treatment and discharge medication in takotsubo cardiomyopathy Acute treatment
Treatment at discharge
β-blockers ▸ Choose one with β-blocking and α-adrenergic receptor blocking properties—not in decompensated patients Diuretics ▸ For volume overload (pulmonary oedema, LVEDP↑) IABP ▸ In cardiogenic shock
β-blockers ▸ Prevent recurrence?
Inotropics ▸ Levosimendan (combined inotropic and vasodilatory action) ▸ Dobutamine or norepinephrine can worsen LVOT obstruction Avoid: QT prolonging drugs Novel drug that need to be tested: ▸ relaxine?
ACE inhibitors or ARBs ▸ In patients with reduced LV function until recovery Anticoagulation ▸ If LV thrombus is present or if severe apical ballooning exists to prevent thrombus formation ASA+statins ▸ If coronary atherosclerosis is present
Antidepressants ▸ Considered in depression and anxiety Novel drugs that need to be tested: ▸ Oestrogen supplementation: to prevent recurrence?
ACE, angiotensin converting enzyme; ASA, acetylsalicylic acid; ARBs, angiotensin receptor blockers; IABP, intra-aortic balloon pump; LVEDP, left ventricular end diastolic pressure; LVOT, left ventricular outflow tract.
Ghadri JR, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304691
catecholamine mediated, and outflow tract obstruction can be worsened. An alternative in many countries is the calcium channel sensitiser levosimendan, which is not currently marketed in the USA. A recent prospective study in 13 patients with TTC and low EF (
