Summary
Background
Takotsubo cardiomyopathy (TTC) continues to be under-diagnosed, due to its varying presentation, with potentially serious consequences if treatment is delayed.
Aims
To demonstrate the consistent involvement of catecholaminergic stress in TTC, regardless of the trigger.
Methods
Between 01 July 2009 and 31 August 2013, patients managed in our centre for thoracic pain syndrome, with or without troponin release, were followed up prospectively. TTC was diagnosed from the apical ballooning seen on left ventricular imaging (angiography or transthoracic echocardiography) in the absence of a significant coronary artery lesion. Triggers (emotional trauma, surgical stress and β2-mimetic intoxication) were recorded; catecholamine-secreting tumours were screened for with a urinary methoxylate-derivative assay.
Results
TTC was diagnosed in 40 out of 2754 (1.5%) patients with thoracic pain syndrome, with or without troponin release. Triggers were emotional trauma ( n = 29, 72.5%), surgical stress ( n = 5, 12.5%), adrenergic intoxication ( n = 3, 7.5%) and catecholaminergic tumour ( n = 3, 7.5%). Mean left ventricular ejection fraction at admission was 38.0 ± 15.7%. Eight (20%) patients initially showed cardiogenic shock. In-hospital mortality was 7.5%, with no deaths from cardiogenic causes. Thirty-five (94.6%) of the survivors had recovered a normal left ventricular ejection fraction (> 55%) by discharge.
Conclusion
Whatever the trigger, the common denominator in TTC is catecholaminergic stress. Classically suggested after emotional trauma, TTC may also be induced by surgical stress or endogenous or iatrogenic β2-mimetic intoxication. The various contexts all have a similarly excellent cardiovascular prognosis if treated early.
Résumé
Contexte
La cardiomyopathie de Takotsubo (CTT) est sous-diagnostiquée ou tardivement du fait des différents types de présentation pouvant conduire à des conséquences potentiellement léthales.
Objectif
Mettre en évidence qu’un stress catécholaminergique est l’unique voie physiopathologique des CTT.
Méthodes
Les patients hospitalisés en unité de soins intensifs pour douleur thoracique avec ou sans libération de troponine entre le 1 er juillet 2009 et le 31 août 2013 ont été suivis. Le diagnostic de CTT était porté devant l’aspect de ballonisation apical (ou médian/basal) du ventricule gauche en l’absence de lésion coronaire. Les facteurs déclenchants étaient identifiés (stress psychologique, contexte péri-opératoire, intoxication bêta-2 mimétique). La présence d’une tumeur catécholaminergique était recherchée par dosage des dérivés méthoxylés urinaires.
Résultats
Le diagnostic de CTT a été porté chez 40 patients pris en charge pour douleur thoracique avec ou sans libération de troponine (40/2754, 1,5 %). Les facteurs déclenchants retrouvés étaient : stress psychologique ( n = 29, 72,5 %) ; péri-opératoire ( n = 5, 12,5 %) ; intoxication bêta-mimétique ( n = 3, 7,5 %) ; et tumeur sécrétante ( n = 3, 7,5 %). La fraction d’éjection moyenne ventriculaire gauche (FEVG) à la prise en charge était de 38,0 ± 15,7 %. La mortalité intra-hospitalière était de 7,5 %. Trente-cinq survivants (94,6 %) avaient retrouvé une fonction ventriculaire normale à la sortie d’hospitalisation.
Conclusions
Peu importe le mécanisme, la décharge catécholaminergique est l’unique voie physiopathologique de la CTT. Le stress psychologique est la description la plus classique mais il est primordial d’évoquer ce diagnostic en cas de dysfonction ventriculaire gauche aiguë dans un contexte péri-opératoire, d’intoxication au beta-mimétique et de rechercher la présence d’une tumeur sécrétante de catécholamines.
Background
Takotsubo cardiomyopathy (TTC) is a rare, but potentially severe, disease that was first defined in 1990 . Several retrospective studies have estimated that 0.7–4.9% of patients presenting with suspected acute coronary syndrome have TTC , and its incidence is estimated to be 29.8 per 1,000,000 inhabitants in a global population . Classically, diagnosis is considered in cases of emotional trauma .
The clinical presentation of TTC may mimic acute coronary syndrome, generally involving chest pain, new electrocardiographical abnormalities and biological abnormalities (release of troponin and creatine kinase [CK]) . Imaging (transthoracic echocardiography, left ventricular [LV] angiography or cardiac magnetic resonance imaging) shows transient LV dysfunction; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution (apical ballooning with an octopus trap [Japanese: takotsubo] pattern). Coronary angiography rules out significant coronary artery stenosis and normal LV systolic function is usually recovered within a few weeks .
The pathophysiology of TTC remains controversial. Epicardial coronary spasm , atheromatous plaque rupture , myocarditis or infarction with healthy coronaries have been suggested, but are now dismissed . Catecholaminergic stress following emotional trauma is presently the hypothesis of choice . However, the current Mayo Clinic criteria require catecholamine-secreting tumour to be ruled out for a diagnosis of TTC.
The aim of the present study was to demonstrate the major involvement of catecholaminergic stress in TTC induced by different triggers.
Methods
Between 01 July 2009 and 31 August 2013, patients managed in our centre for chest pain syndrome and/or troponin release were followed up. TTC was diagnosed exclusively from an LV angiographical or echocardiographical pattern of apical (typical TTC) or medial or basal ballooning (medial or inverse TTC) without significant coronary lesions on angiography. Left ventricular ejection fraction (LVEF) was measured on LV angiography (Axiom Sensis XP; Siemens, Erlangen, Germany) and/or echocardiography using the Simpson biplane method (Vivid E9; GE-Vingmed, Horten, Norway). Two experienced blinded operators analysed segmental kinetics retrospectively from DICOM recordings.
Data were collected on history, cardiovascular risk factors and context of onset (emotional trauma, surgical stress or β2-mimetic intoxication [β+]).
From 01 September 2011, all patients (19/40) underwent complementary screening for catecholamine-secreting tumour (pheochromocytoma/paraganglioma [PCPG]) by urinary methoxylate-derivative high-performance liquid chromatography assay (Chromsystems GmbH, Munich, Germany) within the first 3 days and thoracic-abdominal-pelvic computed tomography or methoxy-isobutyl-isonitrile scintigraphy. Three measurements of 24-hour urinary methoxylate-derivative concentrations were taken during the first 3 consecutive days after admission.
The characteristics of the overall population and various groups were studied according to trigger mechanism: emotional trauma, surgical stress, PCPG or β+. Clinical follow-up comprised functional and therapeutic assessment at 1, 3 and 12 months.
LVEF was assessed by echocardiography and/or LV angiography at initial assessment, and by echocardiography at 7 days, 1 month and 12 months after onset. Troponin and CK concentrations were measured during the initial hospital stay at several time points after TTC onset (6, 12, 24, 48 and 72 hours). Only peak CK and troponin concentrations are presented.
Statistical analysis
Statistical analysis was performed using Stata software, version 12 (StataCorp, College Station, TX, US). The tests were two-sided, with a type I error set at α = 0.05. Baseline characteristics are presented as the mean ± standard deviation or median (interquartile range) for each group for continuous data and as the number of patients and associated percentages for categorical variables. These variables were compared between groups using the Chi 2 or Fisher’s exact test for categorical variables and Student’s t test or the Mann–Whitney test for quantitative variables, with normality verified by the Shapiro–Wilk test and homoscedasticity by the Fisher–Snedecor test. Owing to sample size, non-parametric tests were often preferred. Considering the sample size and univariate results, no multivariable analysis was considered. Finally, to study the evolution of variables at several time points, mixed models, taking into account within and between subject variability, were considered.
Results
Study population characteristics
Between 01 July 2009 and 31 August 2013, 2754 patients were admitted to our centre for chest pain, with or without troponin release. A diagnosis of TTC was confirmed in 40 patients (40/2754, 1.5%; Fig. 1 ). Medical care was initiated at a mean of 9.8 ± 6.2 hours after symptom onset.
History-taking found acute adrenergic stress concomitant with symptom onset: emotional trauma (29/40, 72.5%: including family death [11/29, 37.9%] and physical aggression [3/29, 10.3%]), surgery (5/40, 12.5%: two ears, nose and throat/bronchopulmonary carcinoma resections, one laparoscopic hernia operation, one carotid endarterectomy and one kidney transplant) and adrenergic intoxication (3/40, 7.5%: two overdoses of β2-mimetics for acute asthma and one voluntary intoxication by intravenous adrenalin injection). These last three patients (adrenergic intoxication) were female (aged 27, 60 and 66 years, respectively), with a cardiogenic shock presentation for the youngest (voluntary intoxication by intravenous adrenalin injection). Interestingly, in three (7.5%) patients, elevated urinary methoxylate-derivative concentrations enabled the diagnosis of a catecholamine-secreting tumour (one paraganglioma and two pheochromocytomas) leading to TTC, confirmed by thoracic-abdominal-pelvic computed tomography or methoxy-isobutyl-isonitrile scintigraphy. These three patients (two women and one man, aged 65, 50 and 41 years, respectively) did not exhibit any symptoms of catecholamine-secreting tumour (no hypertension, headaches or palpitations) before the diagnosis of TTC.
Patients with TTC due to emotional trauma were older (68.9 ± 11.7 vs 58.5 ± 14.4 years; P = 0.05) and more were female (29/29 [100%] vs 6/11 [54.5%]; P = 0.001) compared with patients in the three other groups (surgery, β+ and PCPG). TTC characteristics are shown in Table 1 .
| All patients ( n = 40; 100%) | Emotional trauma ( n = 29; 72.5%) | Surgical stress ( n = 5; 12.5%) | β+ ( n = 3; 7.5%) | PCPG ( n = 3; 7.5%) | |
|---|---|---|---|---|---|
| Mean age (years) | 65.0 ± 13.0 | 67 ± 11.9 | 63.5 ± 1.7 | 51 ± 21 | 56.5 ± 9.2 |
| Men/women (n/n) | 6/34 | 0/29 | 4/1 | 0/3 | 2/1 |
| CVRFs | |||||
| Hypertension | 17 (42.5) | 14 (48.3) | 2 (40.0) | 0 | 1 (33.3) |
| Smoking | 12 (30.0) | 8 (27.6) | 2 (40.0) | 1 (33.3) | 1 (33.3) |
| Diabetes | 3 (7.5) | 3 (10.3) | 0 | 0 | 0 |
| Dyslipidaemia | 6 (15.0) | 5 (17.4) | 1 (20.0) | 0 | 0 |
| Familial history of CAD | 5 (12.5) | 4 (13.8) | 0 | 0 | 1 (33.3) |
| Overweight (BMI > 25 kg/m 2 ) | 8 (20.0) | 7 (24.1) | 0 | 1 (33.3) | 0 |
| Previous treatment | |||||
| Beta-blockers | 5 (12.5) | 5 (17.5) | 0 | 0 | 0 |
| CCBs | 7 (17.5) | 4 (13.8) | 2 (40.0) | 1 (33.3) | 0 |
| ACEIs | 3 (7.5) | 3 (10.3) | 0 | 0 | 0 |
| Clinical presentation | |||||
| Chest pain | 28 (70.0) | 25 (86.2) | 0 | 2 (66.7) | 1 (33.3) |
| APO | 4 (10.0) | 4 (10.0) | 0 | 0 | 0 |
| Cardiogenic shock | 8 (20.0) | 1 (3.4) | 5 (100) | 1 (33.3) | 1 (33.3) |
| History of TTC | 2 (5.0) | 1 (3.4) | 0 | 0 | 1 (33.3) |
| Forms of TTC (n) | |||||
| Typical | 35 | 24 | 5 | 3 | 3 |
| Median | 4 | 4 | 0 | 0 | 0 |
| Inverse | 1 | 1 | 0 | 0 | 0 |
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