Hrev_master [page 26] [Emergency Care Journal 2014; 10:1188] Takotsubo cardiomyopathy: diagnosis in an emergency department Marina Mancini,1 Davide Bartolini,2 Mauro Zanna3 1Department of Emergency Medicine, Villa Scassi Hospital, Local Health Unit 3; 2Department of Cardiology, Villa Scassi Hospital, Local Health Unit 3, Genoa, Italy; 3Chief Medical Officer, Life Support Camp of Al Zubair, Basrah, Iraq Abstract Takotsubo cardiomyopathy (TC) is a reversible cardiomyopathy characterized by transient wall-motion abnormalities of the left ventricle (LV) in the absence of significant obstructive coronary disease. In emergency departments the diagnosis remains a chal- lenge because clinical and electrocardiograph- ic presentation of Takotsubo is quite similar to ST-segment elevation myocardial infarction. We conducted a retrospective descriptive study on 1654 patients admitted to our emergency department from 2006 to 2009 who had a left heart catheterization for a suspected acute coronary syndrome and among them we evalu- ated characteristics on admission of 14 patients with a clinical picture suggestive for a TC. All patients were postmenopausal female. Ten patients (71%) had preceding stressful events and four patients (29%) did not have identifiable stressors. Thirteen patients (93%) presented chest pain and one (7%) syncope. ST-segment elevation was present in six patients (43%). One patient (7%) presented an episode of ventricular fibrillation. All patients presented increased cardiac Troponin T. Initial LV ejection fraction, evaluated by transthoracic echocardiography was 44±10%. Follow-up LV ejection fraction was 61±10%. Six patients (43%) had characteristic apical ballooning and eight patients (57%) had hypokinesia or aki- nesia of the apical or/and midventricular region of the LV without ballooning. Coronary angiography was normal in nine patients (64%) and five (36%) had stenosis <50%. None had complete obstruction of a coronary. Takotsubo syndrome should be considered as a possible diagnosis in patients admitted in an emergency department with a suspected diag- nosis of acute coronary syndrome. Emergency physicians should recognize salient aspects of the medical history at presentation in order to organize appropriate investigations and avoid inappropriate therapies. Introduction Transient left ventricular apical dyskinesia, also known as Takotsubo cardiomyopathy (TC) or stress induced cardiomyopathy is a syn- drome characterized by acute onset of tran- sient extensive akinesia of some portions of the left ventricle (LV) (usually the apical and mid portion), without significant stenosis on the coronary angiography. It is often accompa- nied by typical chest pain, dynamic reversible ST-T segment abnormalities and increased cardiac enzymes disproportionate to the extent of akinesia. This syndrome was first described in Japan.1-4 The name Takotsubo is explained by the LV, which, seen on echocardiography, resembles a Japanese octopus trap with a round bottom and a narrow neck. It is also called stress induced cardiomyopathy or broken heart syndrome because it is often, but not always, associated with a psychologically or stressful event. The cause and the pathogenesis of the syn- drome is still uncertain and many theories have been proposed, such as catecholamine- mediated cardiotoxicity, abnormalities in coro- nary microvascular function and multivessel coronary vasospasm.5,6 The predominance of postmenopausal women suggests that ovarian sex hormones estrogens and progesterone can play a role in Takotsubo. Sex hormones can influence sympathetic activity and coronary reactivity and have a role in the regulation of myocardial contraction.7 The most common presenting symptom of Takotsubo is acute chest pain, but patients may also present with dyspnea, pulmonary edema and more rarely cardiogenic shock.2,8 Clinical presentation of TC mimics acute myocardial infarction (AMI) and often people presented to the emergency department with a suspected acute coronary arterial syndrome. It is impossible to distinguish between these two entities based on symptoms, electrocardio- graphic changes, biochemical markers or echocardiography and only after coronary angiography demonstrating no significant stenosis, diagnosis of Takotsubo syndrome can be suspected. Because the management of Takotsubo in the acute phase is different from the AMI and inadequate treatment can be dan- gerous for the patient, TC should be consid- ered as an alternative diagnosis by physicians working in emergency departments. In this report, we evaluate the clinical fea- tures of fourteen patients presented to our emergency department who underwent an urgent coronary angiography with a suspect of acute coronary arterial syndrome. The clinical picture at the end of investigation was consis- tent with the diagnosis of Takotsubo syn- drome. Materials and Methods From May 2006 to April 2009 we retrospec- tively analyzed 1654 patients presented to the emergency department of Villa Scassi Hospital in Genoa, Italy, who had undergone urgent left heart catheterization immediately or within 24 hours of staying in the emergency depart- ment for a suspected acute coronary syn- drome: new-onset chest pain, electrocardio- graphic abnormalities (ST/T wave abnormali- ties, abnormal Q waves) and/or elevated car- diac biomarkers. Among them, we identified fourteen patients with possible Takotsubo syndrome and we described their features on admission. They were included based on the following findings at cardiac catheterization or transthoracic echocardiography: i) reversible akinesia or diskinesia of the apical and/or midventricular segments of the LV with regional wall motion abnormalities; ii) absence of obstructive coronary artery dis- ease. Clinical characteristics (age, gender, symptoms of presentation, coronary risk fac- tors and preceding stressful events) were recorded for each patient. Cardiac biomarkers, 12 lead electrocardiographic and echocardio- graphic findings on admission in the emer- gency department were recorded. Eleven patients underwent urgent coronary angiogra- phy immediately. Three patients underwent urgent coronary catheterization after a period of 6 hours staying in our emergency depart- ment. Follow-up echocardiography was per- formed in twelve patients. All data are expressed as mean±1 standard deviation. Emergency Care Journal 2014; volume 10:1188 Correspondence: Marina Mancini, Department of Emergency Medicine, Villa Scassi Hospital, Local Health Unit 3, Corso Scassi 1, 16151 Genoa, Italy. Tel. +39.339.2664418 - Fax: +39.010.8492716. E-mail: dott.marina.mancini@gmail.com Key words: Takotsubo cardiomyopathy, acute myocardial infarction, reversible left ventricular ballooning, emergency department. Contributions: the authors contributed equally. Conflict of interests: the authors declare no potential conflict of interests. Received for publication: 15 February 2013 Revision received: 28 November 2013. Accepted for publication: 20 December 2013. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright M. Mancini et al., 2014 Licensee PAGEPress, Italy Emergency Care Journal 2014; 10:1188 doi:10.4081/ecj.2014.1188 No n- co mm er cia l u se on ly [Emergency Care Journal 2014; 10:1188] [page 27] Results Fourteen patients (100%) were women and mean age was 67±7 (range 48 to 80). Ten patients (71%) had hypertension, six patients (43%) were smokers, and one patient (7%) had diabetes mellitus. Possible precipitating factors are listed in Table 1. Ten patients (71%) had preceding stressful events. Four patients (29%) did not have identifiable stressors. The most common symptom of presentation was chest pain (93%). One patient (7%) presented with syn- cope. Electrocardiographic and echocardiographic findings are presented in Table 2. Thirteen patients (93%) had electrocardiographic abnormalities at time of presentation; one patient (7%) had a normal electrocardiogram. ST-segment elevation was present in six patients (43%): five (36%) in precordial leads and one (7%) in limb leads. One patient (7%) with ST-segment elevation presented an episode of ventricular fibrillation. Five patients (36%) had T-wave inversion and one (7%) pre- sented pathologic Q waves. One patient (7%) presented non-specific repolarization changes. Initial cardiac Troponin T was increased in all patients (100%) on admission (0.34±0.46 ng/mL, normal <0.010 ng/mL). The initial assessment of LV ejection fraction was per- formed by transthoracic echocardiography. Initial LV ejection fraction was 44%±10%. Apical ballooning characteristic of Takotsubo was observed in six patients (43%). None of the patients had midventricular ballooning or LV outflow tract obstruction. Eight patients (57%) had hypokinesia or akinesia of the api- cal and/or midventricular region of the LV with- out ballooning. Left ventricular ejection frac- tion improved in all 12 patients who underwent follow-up transthoracic echocardiography (61±10%). Coronary angiography was normal in nine (64%) patients and five (36%) had stenosis <50%. None of them needed treat- ment with percutaneous transluminal coro- nary angioplasty. Discussion In 1991 Sato and colleagues describe for the first time a syndrome called Takotsubo syn- drome or transient cardiac ballooning syn- drome.1 It is a condition characterized by tran- sient regional systolic dysfunction of the LV associated with retrosternal pain, ST-segment elevation in the precordial leads, elevated car- diac biomarkers and no significant coronary artery disease detected on coronary angiogra- phy. Subsequently, several cases have been reported in Japan,2-4 and more recently this syndrome began to draw attention worldwide and some reports have documented its pres- ence in other countries.9-11 Because of its clin- ical presentation that often mimics AMI,12-16 patients with Takotsubo are often admitted in emergency departments. Therefore, this is an important and not uncommon entity to be sus- pected and recognized by emergency physi- cians. Reported prevalence among patients with symptoms suggestive of suspected acute coronary syndrome ranges from 0.7 to 2.5%.17 In this single-center case series, we report on our experience of fourteen patients with clini- cal features suggestive for a Takotsubo syn- drome including electrocardiographic abnor- malities and elevated cardiac biomarkers com- patible with myocardial ischemia. They repre- sent 0.8% of patients admitted to our emer- gency department who had a left heart catheterization for suspected acute coronary syndrome. All patients in our series are menopausal female (mean age at presentation was 67±7 years) and this is consistent with the published literature.17 In accordance with literature, the most frequent symptom on pres- entation among our patients is sudden chest pain (93%). One patient (7%) presented with syncope.8,18-20 A peculiar feature of this syndrome is the occurrence of an emotionally or physically stressful event before the onset of symptoms. Triggering events included emotional condi- tions as death of spouse, child, or close family member, domestic abuse, receiving news of serious diagnosis, public performance, losing money, loss of job, occupational stress.17,20 Reported physical stress triggers are external injury, heavy labor, travel, hip fracture, asthma, pneumothorax, cerebrovascular accident and intense physical exercise.10,17,20 However, in 30% there was no preceding emotional or phys- ical stressful event identified. In the present analysis, a stressor event was identifiable in ten patients (71%). Reported cardiovascular risk factors associ- ated to Takotsubo are arterial hypertension, diabetes mellitus, dyslipidemia and current or past smoking.2,4,17 In our report, ten patients (71%) have a history of hypertension, six (46%) are current or past smokers, two (15%) have diabetes and two (15%) have dyslipi- demia. On presentation, electrocardiographic char- acteristics of Takotsubo are similar to that observed in patients with myocardial infarc- tion. The most frequent findings on the admission are ST-segment elevation in precor- dial leads which occurs in approximately 50 to 60% of patients and T-waves inversion in most leads.2,8,9,16,19 In our patients, ST-segment eleva- tion was present in 46% and T-wave inversion in 38% of patients. One patient (7%) developed Article Table 1. Triggers of Takotsubo. Type of stress No. of patients Physical (intense physical exercise, trauma, renal colic) 4 Emotional (death of family member, quarrelling, receiving news of husband’s 6 serious diagnosis, financial instability, husband’s stroke) Unidentified 4 Table 2. Electrocardiographic and echocardiographic parameters on admission. Variable Value (%) ECG ST-segment elevation 6 (43) T-wave inversion 5 (36) Non specific repolarization changes 1 (7) Pathologic Q waves 1 (7) Right bundle branch 1 (7) First degree atrioventricular block 1 (7) Prolonged corrected QT interval in lead V3 1 (7) Ventricular fibrillation 1 (7) Echo Initial LV ejection fraction (%) 44±10 Presence of apical ventricular ballooning 6 (43) Presence of midventricular ballooning 0 LV outflow tract obstruction 0 ECG, electrocardiography; Echo, echocardiography; LV, left ventricle. No n- co mm er cia l u se on ly [page 28] [Emergency Care Journal 2014; 10:1188] pathologic Q-wave in anteroseptal leads; one patient (7%) presented non-specific repolar- ization changes. Previous reports describe that the corrected QT interval can be temporarily prolonged,13,14 but life-threatening arrhythmias are uncommon despite marked, structural abnormalities.21 Corrected QT interval was pro- longed only in one (7%) of our patients. One patient admitted to our emergency department with chest pain and a slight ST-segment eleva- tion in anteroseptal leads (Figure 1) during the medical examination presented an episode of ventricular fibrillation (Figure 2). Defibrillation with 200 Joule was given and the rhythm reverted to normal sinus rhythm after the first shock. Although there are reports about the possi- bility to distinguish Takotsubo from anterior AMI,13,14,22-24 electrocardiographic changes themselves do not have sufficient predictive value for discriminating Takotsubo from AMI. Neither cardiac enzymes are helpful: some patients have no rise in cardiac biomarkers, but most have a slight elevation, usually dis- proportionate to the extent of akinesia of the LV.25 In our study all patients showed a widely variable elevation of troponin T. The echocardiographic findings in Takotsubo are more typical: akinesia of the LV apex, hypercontraction of the basal segments and midventricular hypokinesia causing apical ballooning and reduced LV ejection fraction (20-40%). The wall motion abnormality typical- ly extends beyond the distribution of any one coronary vessel. The apical ballooning is rapid- ly reversible and normalization of the echocar- diogram is usually seen within four to eight weeks.4,8 The baseline LV ejection fraction in our population is 44±10% and the typical api- cal ballooning was present in 43% of our patients. Of the fourteen patients, twelve had follow-up ejection fraction determination and all of them had an improvement in their LV ejection fraction (61±10%). There are reports about Takotsubo variants in which the middle segments of the ventricle balloons during sys- tole, called midventricular ballooning, inverted Takotsubo pattern or non apical ballooning.26 None of our patients shows non apical balloon- ing. On the basis of demographic and clinical features, electrocardiographic and echocardio- graphic findings and laboratory abnormalities, emergency physicians should consider a possi- ble diagnosis of Takotsubo. Nevertheless, in order to definitely distinguishing Takotsubo from an AMI, urgent coronary angiography is necessary. Typically, patients with stress induced cardiomyopathy have normal coronary arteries or occasionally mild irregularities.15 In accordance, nine (64%) of our patients have normal coronary angiography and five (36%) had <50% stenosis. The diagnostic criteria for Takotsubo remain controversial. The proposed modified Mayo Clinic criteria16 for the clinical diagnosis of Takotsubo are shown in Table 3. These crite- ria are entirely satisfied by our patients. It is to note that the possibility that patients with obstructive coronary atherosclerosis develop Takotsubo has been recently reported. Therefore some authors proposed that the sec- ond Mayo Clinic diagnostic criterion be replaced with a large discrepancy between dys- kinetic segments and coronary lesions on the angiogram, either qualitative (different vascu- lar territories) or quantitative (segmental extension).27 Others suggested changing the second criterion to a nonobstructive coronary disease of less than 50% stenosis.28 Because the pathophysiology is unclear and major prospective randomized controlled trials are absent, optimal treatment for Takotsubo Article Table 3. Proposed Mayo Clinic criteria for the clinical diagnosis of Takotsubo cardiomyopathy. Criteria Reversible LV dysfunction, with RWMA not confined to a particular epicardial coronary artery irrigation area° Exclusion of angiographic evidence of obstructive coronary artery disease, or ruptured plaque New ECG abnormalities and/or elevated troponin Absence of recent head trauma, intracranial hemorrhage, pheochromocytoma, myocarditis, hypertrophic cardiomyopathy LV, left ventricle; RWMA, regional wall motion abnormality; ECG, electrocardiography. °However, some patients can have atypical Takotsubo cardiomyopathy with RWMA confined to a single coronary area; therefore the judgement requires additional factors indicated as in rows below. Figure 1. Twelve-leads electrocardiography in a patient on admission. Figure 2. Episode of ventricular fibrillation reverted to sinus rhythm after a 200 Joule shock. No n- co mm er cia l u se on ly [Emergency Care Journal 2014; 10:1188] [page 29] has yet to be established. Therefore, at pres- ent, treatment is mainly symptomatic and sup- portive. Because the presentation is indistin- guishable from an acute coronary syndrome, in an emergency department the treatment should be directed toward the myocardial ischemia. Aspirin, cardioselective b-blockers and ACE-inhibitors have been used during the LV dysfunction. b-blockers were also suggested as treatment to prevent malignant arrhyth- mias. If LV outflow tract obstruction is a pre- dominant feature intravenous fluid with short acting b-blockers should be cautiously admin- istered to decrease contractility and increase LV cavity size. Severe cardiogenic shock should be treated with an intra-aortic balloon pump or inotropic support.20 The overall prognosis is favorable. The most frequent complication is left-sided heart fail- ure. In the acute phase, deaths due to cardio- genic shock, ventricular fibrillation, ventricu- lar rupture, mitral valve dysfunction and pul- monary embolism are reported. Reported recurrence rate of Takotsubo is very low.20 Conclusions The frequency of the diagnosis of TC has increased over the past few years, perhaps due to increasing awareness among cardiologists. In the most of cases, emergency physicians are the first to manage with these patients and thus it is an important entity they have to know and to understand, especially at present when the emergency physician is increasingly tak- ing much more autonomy in diagnostic and therapeutic management of patients. At initial presentation the diagnosis of Takotsubo syndrome remains a challenge because of the similarity between this syn- drome and that of ST elevation myocardial infarction (STEMI). It is a necessary recogni- tion of salient aspects of the medical history and a high index of suspicion for thinking about stress induced cardiomyopathy. At presentation symptoms, electrocardio- graphic features and cardiac enzymes may not be conclusive. An urgent transthoracic echocardiography can be performed and the feature of a characteristic apical ballooning can be useful for the diagnosis, but the associ- ation of Takotsubo with contraction patterns not strictly conforming to the original descrip- tion make it more difficult to diagnose. The suspicion of Takotsubo can be confirmed, in most of cases, by an urgent coronarography. It is important differentiating Takotsubo from an AMI, not only because the outcome is different, but also for avoiding inadequate treatment in the acute phase. This is crucial for emergency physicians working in an institution without primary percutaneous coronary intervention and for physicians working in prehospital set- ting, when fibrinolytic therapy is considered for a possible STEMI because inappropriate administration of fibrinolytics to a patient with Takotsubo may lead to potential heavy risks as bleeding complications, acute renal failure and others. 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