In 1990 in Japan, a syndrome was described consisting of chest pain, electrocardiographic and biochemical changes similar to those seen in acute myocardial infarction, and abnormalities of left ventricular apical contractility.1 The peculiarity of this new disease, which was first attributed to multivessel spasm, was that the coronary arteries showed no lesions and the marked abnormalities of ventricular segments virtually resolved within a few days or weeks.1,2 The syndrome was named tako-tsubo cardiomyopathy (TCM), apical ballooning, or transient apical dyskinesia. Compared with classic coronary syndromes, TCM is notable for regional involvement of various coronary territories and its excellent ultimate prognosis.2,3 Nonetheless, although it is usually a benign condition, it is not without complications. The most common of these are heart failure, arrhythmia, intraventricular thrombi, and even death, mainly occurring in the acute phase.4

Various groups from Spain and other countries have reported case series consistent with these features,1–6 including a description of the first series in Spain of the midventricular variant,7 which is also recognized outside our country.3 Other related articles from Spain have described patients with predominantly inferior ventricular involvement, and one has proposed the theory that the condition coincides with chronic ischemic heart disease.8 Some authors have focused on the relationship between the left ventricular hypertrophy and the mid- to long-term outcome of these patients,4 which may not be as benign as that of other patients with hypertrophic ventricles.9 In addition, Spanish researchers have intensively investigated the pathophysiology of the syndrome and have proposed some interesting theories in this line, such as a wraparound left anterior descending artery,5 or an effect of the intraventricular pressure gradient.9 Other studies have compared the electrocardiographic findings according to race.6,10

Several hypotheses have been proposed to explain the etiopathogenesis of TCM.11–14 Although it remains to be clarified, there seems to be an important relationship between the development of this syndrome and an excess of circulating catecholamines resulting from a situation of emotional or physical stress.4,11 Nonetheless, the definitive cause of TCM is uncertain and precise epidemiologic data on this condition are not available in Spain, as most of the published articles report the experience of one or only a few centers.

The aim of this study was to create a collaborative, multicenter national registry of TCM cases with a view to describing this disease in more detail in our setting.

The multicenter Spanish REgistry for TAKOtsubo cardomyopathy (RETAKO), created under the auspices of the Ischemic Heart Disease and Cardiovascular Acute Care Section of the Spanish Society of Cardiology, is a prospective, voluntary, national registry. It includes patients who meet the criteria for this disease (based on the modified Mayo criteria15) in the opinion of the attending physicians, as reported previously.4 The present analysis included data on TCM patients consecutively hospitalized from (and including) 1 January 2012 to 31 December 2013, provided by 23 hospitals throughout the country (Table 1). The number of patients with this condition relative to the number of coronary angiographies requested in each hospital for the working diagnosis (subsequently confirmed or not) of acute coronary syndrome was calculated to determine the approximate incidence of this disease in our setting. The Registry collected information on the patients’ clinical characteristics, complications during hospitalization, analytical results, and findings on electrocardiography, echocardiography, and other imaging techniques (magnetic resonance imaging was optional in the protocol). Initially, this information was recorded on a case report form and sent by e-mail to a data processing center, whereas later (after 2014), it was directly recorded on an on-line case report form. Some variables with aspects that were difficult to systematize were recorded on an open text field. To be included in the Registry, patients had to have undergone invasive coronary angiography that excluded significant obstructive lesions (> 50%) and any other potential cause of the clinical symptoms (eg, thrombus, dissection, ulcer). The treatment prescribed was always at the discretion of the attending physicians. At least 2 follow-up visits were recommended, one at 3 months and another at 1 year following the index event. Complete resolution of the regional wall motion abnormalities by any imaging technique was required, except in cases of death before the visit. The objectives investigated over follow-up were cardiovascular death, death due to any cause, and the need for readmission for any cause in a cardiology service. The study was approved by the Ethics Committee of Hospital Clínico San Carlos, and patients gave informed consent to participate in the Registry.

The RETAKO is the largest TCM series compiled in Spain, containing first-hand information from the physicians treating these patients. Despite the limitations associated with a disease having a very low incidence and cases scattered across the country, the registry data provide a very close idea of the epidemiology of TCM in our setting. The characteristics of our patients are quite similar to those reported in series from other geographic areas.12,15–22 There is a predominance of hypertensive, postmenopausal women, and the common complications during admission include heart failure, arrhythmias (mainly supraventricular, but also ventricular), renal failure, iatrogenic complications, and others derived from the comorbidities.4 Although an outcome analysis was not the aim of this study because of the short follow-up period, we observed a generally favorable outcome following hospital discharge, as described in other studies.4

The etiopathogenesis of TCM remains speculative. Despite some evidence from intracoronary imaging,23,24 angiographically-silent plaque rupture as a causal possibility is uncertain; hence, a number of etiologies have been suggested for the syndrome.4 One of the most widely accepted theories in the scientific community for the transient ventricular dysfunction is the influence of catecholamines and the distribution of myocardial beta-receptors.11,12 Other hypotheses have recently been proposed, such as microcirculation vasospasm, based on a detection of an endothelin-1 abnormality.25 The contribution of this factor is difficult to reliably define; further knowledge of the disease is needed to definitively confirm this possibility.

The information derived from this registry and previous series gives the impression that the syndrome known as TCM may be a catch-all encompassing quite varied origins from a situation of myocardial stunning. Cases have been described in almost every imaginable circumstance involving stress, including the classic grieving for the death of a loved one, a fall with inability to get up for some hours, an asthma attack, pulmonary embolism, surgery, dysthyroidism, cerebrovascular disease, and even catecholamine administration during stress testing.16,26,27 Other pertinent questions also require clarification: why is it that not all people who go through stressful situations experience the syndrome? and Why is it that people who have had one episode of TCM do not have another in new situations of intense stress? (recurrence is uncommon).

Moreover, in a considerable number of cases (40-50%) in our series and in the literature, no potential triggering factor could be identified even after careful questioning. Could these be a primary form? This might be relevant from the prognostic standpoint, since it seems that patients with more severe diseases or comorbidities (secondary forms?) may have a poorer outcome, with the underlying or concomitant disease being the determinant of the poorer prognosis.28 At this time, however, it is difficult to say whether the prognosis is marked by the comorbidities or the triggering factors, although it is likely that both play a part. It is important to interpose this consideration in the decision of where to hospitalize the patient. If there are no comorbid conditions (or “secondary” form), the clinical status is good, and the ventricular dysfunction and biomarker elevations are not severe, it may be a safe choice to admit the patient for a few days to a hospital ward. In our cohort, 4 of the 5 deaths were due to causes unrelated to TCM. Of course, this reflection should be confirmed in larger TCM series with rigorous data collection. In summary, TCM has gained sufficient importance in recent years to merit a place in several clinical guidelines; for example, the European guidelines for the diagnosis and treatment of acute and chronic heart failure of 2012, in which it still appears as an unclassified cardiomyopathy.29 In this line, RETAKO will continue its activity, attempting to respond with greater accuracy to the questions that arise about this enigmatic disease or group of diseases.

Tako-tsubo cardiomyopathy is an uncommon disease that predominantly affects postmenopausal women and occurs following an emotionally stressful situation in half the cases. It is generally characterized by anginal chest pain and shows no weekly or seasonal distribution pattern. The acute phase is not without complications or mortality, but once it has passed, the condition usually has a favorable outcome.

This project was partially funded by a grant from the FMMA (Fundación Mutua Madrileña Automovilista). The electronic case report form and the RETAKO website31 were funded by AstraZeneca.

None declared.