ORIGINAL RESEARCH published: 14 March 2022 doi: 10.3389/fcvm.2022.742010 Differences Between Takotsubo and the Working Diagnosis of Myocardial Infarction With Nonobstructive Coronary Arteries Edited by: Turgay Celik, Javier Lopez-Pais 1*, Bárbara Izquierdo Coronel 2 , Sergio Raposeiras-Roubín 3 , VM Medical Park Ankara, Turkey Leyre Álvarez Rodriguez 4 , Oscar Vedia 5 , Manuel Almendro-Delia 6 , Alessandro Sionis 7 , Reviewed by: Agustin C. Martin-Garcia 8 , Aitor Uribarri 9 , Emilia Blanco 10 , Irene Martín de Miguel 11 , Philippe Commeau, Emad Abu-Assi 3 , David Galán Gil 2 , Manuela Sestayo Fernández 4 , Polyclinique Les Fleurs Groupe Maria Jesús Espinosa Pascual 2 , Rosa María Agra-Bermejo 4 , Diego López Otero 4 , ELSAN, France Jose María García Acuña 4 , Joaquín Jesús Alonso Martín 2 , Francesco Santoro, University of Foggia, Italy Jose Ramón Gonzalez-Juanatey 4 , Miguel Ángel Perez de Juan Romero 1 and Ricardo Sanz-Ruiz, Iván J. Núñez-Gil 5 on behalf of the RETAKO investigators Gregorio Marañón Hospital, Spain 1 Cardiology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain, 2 Cardiology Department, Karin Gunilla Schenck-Gustafsson, Hospital Universitario de Getafe, Madrid, Spain, 3 Cardiology Department, Hospital Universitario Álvaro Cunqueiro, Vigo, Karolinska Institutet (KI), Sweden Spain, 4 Cardiology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain, *Correspondence: 5 Cardiology Department, Hospital Clínico San Carlos, Madrid, Spain, 6 Cardiology Department, Hospital Universitario Virgen Javier Lopez-Pais Macarena, Sevilla, Spain, 7 Cardiology Department, Hospital de Sant Pau, Barcelona, Spain, 8 Cardiology Department, javierlopezpais@gmail.com Hospital Clínico Universitario de Salamanca, Salamanca, Spain, 9 Cardiology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain, 10 Cardiology Department, Hospital Arnau de Vilanova, Lérida, Spain, 11 Cardiology Department, Specialty section: Hospital General Universitario Gregorio Marañón, Madrid, Spain This article was submitted to Coronary Artery Disease, a section of the journal Aim: Whether Takotsubo syndrome (TTS) should be classified within myocardial Frontiers in Cardiovascular Medicine infarction with non-obstructive coronary arteries (MINOCAs) is still controversial. The aim Received: 15 July 2021 of this work was to evaluate the main differences between TTS and non-TTS MINOCAs. Accepted: 20 January 2022 Published: 14 March 2022 Methods and Results: A cohort study based on two prospective registries: TTS from Citation: the RETAKO registry (N:1,015) and patients with non-TTS MINOCAs from contemporary Lopez-Pais J, Izquierdo Coronel B, records of acute myocardial infarction from five 5 national centers (N:1,080). Definitions Raposeiras-Roubín S, Álvarez Rodriguez L, Vedia O, and management recommended by the ESC were used. Survival analysis was based Almendro-Delia M, Sionis A, on the Cox regression analysis; propensity score matching (PS) was created to adjust Martin-Garcia AC, Uribarri A, prognostic variables. Takotsubo syndrome were more often women (85.9 vs. 51.9%; p Blanco E, Martín de Miguel I, Abu-Assi E, Galán Gil D, Sestayo < 0.001) and older (69.4 ± 12.5 vs. 64.5 ± 14.1 years; p < 0.001). Atrial fibrillation Fernández M, Espinosa Pascual MJ, (AF) was more frequent in non-TTS MINOCAs (10.4 vs. 14.4%; p = 0.007). Psychiatric Agra-Bermejo RM, López Otero D, García Acuña JM, Alonso Martín JJ, disorders were more prevalent in TTS (15.5 vs. 10.2%, p < 0.001). In-hospital mortality Gonzalez-Juanatey JR, Perez de Juan and complications were higher in TTS: 3.4 vs. 1.8%, (p = 0.015), and 25.8 vs. 11.5%, Romero MÁ and Núñez-Gil IJ (2022) (p < 0.001). Global mortality before PS matching was 16.1% in non-TTS MINOCAs and Differences Between Takotsubo and the Working Diagnosis of Myocardial 8.1% in TTS. Median follow-up was 32.4 months; after PS matching, TTS had fewer Infarction With Nonobstructive major adverse cardiovascular events (MACEs): hazard ratio (HR) 0.59; 95% CI 0.42–0.83. Coronary Arteries. Front. Cardiovasc. Med. 9:742010. There were no differences in global mortality (HR 0.87; CI: 0.64–1.19), but TTS had lower doi: 10.3389/fcvm.2022.742010 cardiovascular mortality (HR 0.58; CI: 0.35–0.98). Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 March 2022 | Volume 9 | Article 742010 Lopez-Pais et al. Takotsubo Is Not a MINOCA Conclusion: Compared to the rest of MINOCAs, TTS presents a different patient profile and a more aggressive acute phase. However, its long-term cardiovascular prognosis is better. These results support that TTS should be considered a separate entity with unique characteristics and prognosis. Keywords: Takotsubo, MINOCA, definition, prognosis, working diagnosis KEY POINTS Definition of Infarction (1) and later scientific statements from AHA considers the TTS as a separate entity (20). - What is already known about this subject? This study was developed based on that idea, with the Takotsubo syndrome may be considered as acute objective of comparing TTS to the rest of patients with cardiomyopathy, although it can mimic an acute coronary MINOCAs, searching for differences between them in clinical syndrome. For this reason, it first was included in the working profile and mid-term prognosis. diagnosis of MINOCAs. - What does this study add? Takotsubo syndrome has a different clinical profile that METHODS MINOCAs, with a more aggressive acute phase regardless Retrospective study of two cohorts based on prospective registries of what its long-term cardiovascular prognosis is better as of patients with TTS and AMI, respectively, with the objective of compared with the rest of patients with MINOCAs. comparing a TTS with a non-TTS MINOCAs cohort. INTRODUCTION Study Population Takotsubo Syndrome cohort was based on the National Medicine has never been an exact science. To minimize errors Multicenter Registry on TTS (RETAKO), sponsored by the caused by this inevitable fact, many classifications have been Section of Ischemic Heart Disease and Cardiovascular Acute developed to treat diseases as precisely as possible (1). However, Care of the Spanish Society of Cardiology. It is a prospective and there are still some gaps in evidence, even in deeply studied fields voluntary study, including 24 centers in the country. Its rationale such as acute myocardial infarction (AMI) (2). In the recent and design have been previously described (14), and in summary, decades, scientific societies have developed guidelines to act as it prospectively includes all consecutive patients with TTS who a consensus to standardize best clinical practice (3). Guidelines fulfill the modified Mayo Clinic diagnostic criteria (13): (a) must be clear so that physicians can offer patients the best care transient left ventricular dysfunction with apical, midventricular available. Despite having its chapter in guidelines, myocardial or basal segmental alterations extending beyond the territory infarction with nonobstructive coronary arteries (MINOCAs) supplied by a single coronary artery; (b) absence of significant remains an unclear subject (4–9). This is due to two main facts. obstructive coronary artery disease (luminal narrowing >50%) or At first, many physiopathological mechanisms are underlying angiographic evidence of a complicated atheroma plaque; (c) new the blurred concept of MINOCAs. Second, MINOCAs being electrocardiogram (EKG) changes (ST-segment elevation and/or a “working diagnosis” (4) leads to the paradox that the same negative T-waves) or moderate elevation of cardiac troponins; disease could be a MINOCAs or not depending on the time (d) absence of myocarditis or pheochromocytoma (13, 14). of diagnosis. Complete normalization of wall motion abnormalities and left Myocardial infarction with nonobstructive coronary arteries ventricular ejection fraction (LVEF) was required, except in the represent a considerable percentage of all the AMI (5–14% of all event of death. For this analysis, 1,055 subjects with TTS were the AMI undergoing coronary angiogram) (4, 5, 10, 11). Recent consecutively included between January 1, 2003, and December publications suggest that MINOCAs prognosis is worse than 31, 2017. The closing date to follow-up was settled on September previously considered, with first-year mortality reaching up to 30, 2018. 5% (12) and the proportion of MACE around 20% (9). One of the The non-TTS MINOCAs cohort was created with all traditional mechanisms of MINOCAs was Takotsubo syndrome consecutive patients admitted for AMI in five national centers (TTS) (1, 4, 11, 13–15), a transient ventricular dysfunction that during the same period (2003–2017, follow-up settled on mimics an AMI in the absence of coronary obstruction (16, September 2018). After excluding patients with TTS, 1,080 17). TTS pathophysiology remains unclear. However, with the patients were classified as MINOCAs according to the ESC available evidence, it seems that dysregulation in sympathetic Position Paper on MINOCAs (4): AMI according to the 3rd neurohormonal axis plays a vital role, leading, somehow, to Universal Definition of Infarction (which equals to type 1 MI in endothelial dysfunction and vasospasm (18–20). This hypothesis the 4th Universal Definition of Infarction) (1, 21); and coronary suggests that even in the acute phase, TTS is a phenocopy of an arteries without significant angiographic obstruction (meaning AMI, its notion may be closer to an acute myocardiopathy than <50% of stenosis). In order to obtain a working diagnosis for to an AMI. The 2016 position paper from ESC includes the TTS MINOCAs, there could not be any other obvious explanation in the definition of MINOCAs (4), whereas 2018 4th Universal for the event at the moment of its presentation; this fact was Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 March 2022 | Volume 9 | Article 742010 Lopez-Pais et al. Takotsubo Is Not a MINOCA confirmed in every case after a thorough review carried out by reported with 95% CIs. A two-sided P value of <0.05 was trained cardiology staff. considered statistically significant. Patients referred for coronary angiography only to rule out coronary disease in the context of another entity, were not included in the study (pulmonary emboli, aortic stenosis, RESULTS hypertrophic myocardiopathy, myocarditis). Patients initially treated and managed as an AMI, but that later happened to Baseline Comparison have myocarditis confirmed by magnetic resonance, were not Patients with TTS, as compared with non-TTS MINOCAs, were classified as MINOCAs, following the 4th Universal Definition more frequently women (p < 0.001), older (69.4 ± 12.5 vs. 64.5 of Infarction. Patients who fitted the new definition of acute ± 14.1; p < 0.001), with a higher prevalence of hypertension myocardial damage (1) were excluded. and no significant differences regarding the rest of cardiovascular Standardized forms were used for the setting-up of the risk factors. Despite that, AF was more frequent in non-TTS database, including demographical information, epidemiological MINOCAs (10.4 vs. 14.4%; p = 0.007). Psychiatric disorders were data, drugs received during hospital admission and at discharge more prevalent in individuals with TTS (15.5 vs. 10.2%, p < attending to criteria of the physician, and other relevant 0.001). During hospitalization because of other causes, TTS was clinical information. This study considered the presence of AF an intercurrent complication in 22.4% of the cases as compared both when it was diagnosed during hospitalization and as a with 0.8% in the non-TTS group (p < 0.001). Details of baseline prior antecedent of this arrhythmia. Psychiatric diagnoses were characteristics are summarized in Table 1. considered, according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (22). All in-hospital complications and in-hospital mortality were registered. TABLE 1 | Baseline characteristics. Follow-Up and Outcomes Variables Takotsubo patients Non-takotsubo P-value Follow-up analysis included: MACE (a composite of a recurrence N:1,015 MINOCA patients of AMI, transient ischemic attack (TIA)/stroke, or death N:1,080 from cardiovascular cause), time to first readmission from Age 69.4 ± 12.5 64.5 ± 14.1 < 0.001 cardiovascular causes, cardiovascular mortality (caused by Female sex 872/1,015 (85.9%) 561/1,080 (51.9%) < 0.001 myocardial infarction, sudden death, heart failure, or other Cardiovascular risk vascular causes) and death from any cause. Follow-up data factors were collected via clinical visits, medical records, institutional Smoking 259/1,015 (25.5%) 274/1,080 (25.4%) 0.9 databases, or telephone interviews. Data was censored at 8 years. Diabetes 181/1,015 (17.8%) 186/1,080 (17.2%) 0.7 If a possible prespecified outcome was observed, a review of Dyslipidemia 449/1,015 (44.2%) 516/1,080 (47.8%) 0.1 electronic medical records by experienced local investigators was Hypertension 654/1,015 (64.4%) 645/1,080 (59.7%) 0.02 mandatory for event adjudication. This study was approved by Cardiovascular the institutional review board and followed the tenets of the history Declaration of Helsinki. ACVA 53/1,015 (5.2%) 63/1,080 (5.8%) 0.5 AF or flutter 106/1,015 (10.4%) 155/1,080 (14.4%) 0.007 Statistical Analysis PVD 42/1,015 (4.1%) 49/1,080 (4.5%) 0.6 Statistical analysis was performed with the IBM SPSS 24.0 Comorbidities software (SPSS Incorporation, Chicago, Illinois, USA) with Chronic kidney 66/1,015 (6.5%) 85/1,080 (7.9%) 0.2 the essentials for R-3.2 package and the propensity score disease (PS) matching patch 3.04. Continuous variables are presented OSAHS 29/1,015 (2.9%) 27/1,080 (2.5%) 0.6 as means and SDs or as medians with SD or interquartile Active cancer 113/1,015 (11.1%) 107/1,080 (9.9%) 0.3 range, as appropriate. Categorical variables are provided with Autoimmune disease 67/1,015 (6.6%) 64/1,080 (5.9%) 0.5 percentages. Pearson chi-square or Student t-tests and their Connective tissue 12/1,015 (1.2%) 10/1,080 (0.9%) 0.5 nonparametric equivalent were used depending on the variable disease type. A PS was created to adjust for baseline differences Psychiatric illness 157/1,015 (15.5%) 110/1,080 (10.2%) < 0.001 between subjects with and patients with non-TTS MINOCAs Migraine 34/1,015 (3.3%) 9/1,080 (0.8%) < 0.001 (Supplementary Table 1). A logistic regression model with TTS Intercurrent 227/1,015 (22.4%) 9/1,080 (0.8%) < 0.001 as outcome was used to generate PSs for all the subjects, using complication* a bond 1:1 matching with a caliper of 0.01. Variables that Cocaine abuse 5/1015 (0.5%) 5/1080 (0.5%) 0.9 are main potential risk factors for cardiovascular events (age, hypertension, diabetes, tobacco, and dyslipidemia) were included Values are mean ± SD or n (%). ACVA, acute cerebrovascular accident; AF, atrial fibrillation; PVD, peripheral vascular in the model. Time to event of the primary outcomes was disease; OSAHS, obstructive sleep apnea/hypopnea syndrome; MINOCA, myocardial analyzed with Cox regression analysis using the 1:1 matching infarction with nonobstructive coronary arteries. based on the PS. Odds ratios and Hazard ratios (HRs) are *While hospitalization for another cause. Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 March 2022 | Volume 9 | Article 742010 Lopez-Pais et al. Takotsubo Is Not a MINOCA TABLE 2 | Main clinical data and test findings. TABLE 3 | Complications during hospitalization. Variables Takotsubo patients Non-takotsubo P-value Variables Takotsubo patients Non-takotsubo P-value N:1,015 MINOCA patients N:1,015 MINOCA patients N:1,080 N:1,080 Data at admission Total 262/1,015 (25.8%) 124/1,080 (11.5%) < 0.001 Killip-Kimball III or IV 209/1,055 (19.8%) 38/1,080 (3.5%) < 0.001 Acute pulmonary edema 217/1,015 (21.4%) 45/1,080 (4.2%) < 0.001 Heart rate 83.99 ± 14.66 80.67 ± 24.30 0.001 Cardiogenic shock 121/1,015 (11.9%) 31/1,080 (2.9%) < 0.001 Systolic blood pressure 128.12 ± 29 137.76 ± 28.16 < 0.001 Reinfarction 4/1,015 (0.4%) 7/1,080 (0.6%) 0.4 (mmHg) Major bleeding event 35/1,015 (3.4%) 56/1,080 (5.2%) 0.05 Laboratory ACVA 27/1,015 (2.7%) 8/1,080 (0.7%) 0.001 Troponine T (ng/L) 485.00 3.74 (0.46–25.42) < 0.001 Recovered cardiac arrest 5/1,015 (0.5%) 9/1,080 (0.8%) 0.4 (94.25–946.75) Mechanical complications 3/1,015 (0.3%) 1/1,080 (0.1%) 0.3 Troponine I (ng/ml) 2.7 (1.05–5.60) 0.50 (0.12–3.46) 0.02 In-hospital mortality 35/1,015 (3.4%) 19/1,080 (1.8%) 0.015 CK (U/L) 62.0 (15.4–236.5) 184.0 (104.5–412.0) 0.75 Haemoglobine (g/dL) 13.17 ± 2.26 13.90 ± 4.52 0.001 ACVA, acute cerebrovascular accident. Leucocytes 10.64 ± 4.61 10.31 ± 29.58 0.81 C-reactive protein 12.00 3.00 (0.57–8.00) 0.02 TABLE 4 | Treatment at discharge. (mg/L) (3.00–54.5.00) NT-proBNP (pg/mL) 3,600.0 1,241.0 < 0.001 Variables Takotsubo patients Non-takotsubo P-value (1,621.0–9,001.5) (386.5–2,848.0) N:1,015 MINOCA patients Creatinine (mg/dL) 1.09 ± 0.83 1 ± 0.62 0.03 N:1,080 Electrocardiogram Acetyl salicylic acid 48/1,015 (4.7%) 733/1,080 (67.9%) < 0.001 Abnormal EKG 785/1,015 (77.3%) 348/1,080 (32.2%) < 0.001 Dual antiplatelt therapy 10/1,015 (1.0%) 254/1,080 (23.5%) < 0.001 ST segment elevation 517/1,015 (50.9%) 85/1,080 (7.9%) < 0.001 Anticoagulants 173/1,015 (17.0%) 186/1,080 (17.2%) 0.9 Non-ST segment 138/1,015 (13.6%) 91/1,080 (8.4%) < 0.001 elevation Beta-blockers 592/1,015 (58.3%) 570/1,080 (52.8%) 0.01 Negative T waves 333/1,015 (32.8%) 126/1,080 (11.7%) < 0.001 ACE inhibitors/ARB 604/1,015 (59.5%) 540/1,080 (50.0%) < 0.001 Echocardiogram Nitrates 42/1,015 (4.1%) 10/1,080 (0.9%) < 0.001 Left ventricular ejection 42.1 ± 13.11 56.09 ± 10.20 < 0.001 Diuretics 233/1,015 (23.0%) 90/1,080 (8.3%) < 0.001 fraction Calcium antagonists 90/1,015 (8.9%) 148/1,080 (13.7%) < 0.001 Left ventricular 747/1,015 (73.6%) 308/1,080 (28.5%) < 0.001 Statins 503/1,015 (49.6%) 822/1,080 (76.1%) < 0.001 dysfunction MINOCAs, myocardial infarction with nonobstructive coronary arteries; ACEI/ARB, Moderate to severe 313/1,015 (30.8%) 196/1,080 (18.1%) < 0.001 angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. valvulopathy Pulmonary hypertension 158/1015 (15.6%) 13/1080 (1.2%) < 0.001 MRI performed 266/1,015 (26.2%) 56/1,080 (5.2%) < 0.001 Days of 6.0 (4.0–10.0) 7.0 (5.0–12.0) < 0.001 hospitalization (infarction, pulmonary edema, shock, stroke, hospitalization hemorrhages, mechanical complications) occurred in 25.8% of patients with TTS as compared with 11.5% of non-TTS (p < Values are mean ± SD, median (P25-P75), or n (%). Hear rate expressed in beats 0.001). In-hospital mortality was higher in patients with TTS per minute. MINOCA, myocardial infarction with nonobstructive coronary arteries. (3.4 vs. 1.8%, p = 0.015). Details of the analysis are provided in Table 3. Clinical Presentation Treatment At presentation, 19.8% of patients with TTS arrived on Killip– Regarding treatment at discharge (Table 4), dual antiplatelet Kimball class III or IV as compared with 3.5% in the non- therapy (DAT) was prescribed in 1.0% of patients with TTS TTS (p < 0.001). Heart rate in individuals with TTS was as compared with 23.5% of non-TTS MINOCAs (p < 0.001), higher, and their systolic blood pressure was lower. Abnormal beta-blocker prescription and angiotensin-converting enzyme EKG was present in 77.3% of patients with TTS as compared inhibitors/angiotensin II receptor blockers (ACEI/ARB) were with 32.2% of non-TTS (p < 0.001). As Table 2 shows, TTS higher in the TTS cohort (58.3 vs. 52.8%; p = 0.011 and 59.5 vs. individuals had higher levels of troponin, natriuretic peptides, 50.0%; p < 0.001, respectively). The prescription of statins was and C-reactive protein. Hemoglobin was lower in patients with lower in individuals with TTS (49.6 vs. 76.1%; p < 0.001). TTS (13.2 ± 2.3 vs. 13.9 ± 4.5, g/decilitre; p < 0.001). The median ejection fraction of patients with TTS was 42.1 ± 13.1% Prognosis Based on Propensity Score as compared with 56.1 ± 10.2% of non-TTS (p < 0.001). Analysis Ventricular dysfunction was more than twofold present in the Median follow-up was 32.4 months [percentile (P) 25: 3.8 TTS group than in non-TTS (p < 0.001). Complications during months, P = 75: 50.1 months]; survival analysis was performed Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 March 2022 | Volume 9 | Article 742010 Lopez-Pais et al. Takotsubo Is Not a MINOCA FIGURE 1 | Follow-up analysis based on a propensity score matching. Kaplan Meier representation of the survival analysis, on them, Cox regression results. In red nontakotsubo MINOCA, in blue Takotsubo syndrome patients. (A) Major adverse cardiovascular events (MACE). (B) Cardiovascular mortality. (C) All-cause mortality. HR, hazard ratio. on the model created with a PS matching to adjust for TABLE 5 | Follow-up survival analysis. baseline differences in variables that are potential arguments for Takotsubo Non- HR C.I. 95% P-value cardiovascular events (age, diabetes, tobacco, hypertension, and MINOCA Takotsubo dyslipidemia). After a bond 1:1 matching (with a caliper of 0.01), Syndrome 745 patients remained in each cohort. MACE (cardiovascular mortality, infarction or TIA/stroke) MACE (%) 6.3 17.4 0.59 0.42–0.83 0.002 were lower in patients with TTS [hazard ratio (HR) 0.59; 95% CV Mortality (%) 2.7 7.8 0.58 0.35–0.98 0.042 CI 0.42 to 0.83]. Individually, both the composite outcomes Infarction (%) 2.4 6.8 0.60 1.34–1.02 0.060 CV mortality and TIA/stroke were lower in patients with TTS TIA or Stroke (%) 1.1 4.6 0.44 0.21–0.96 0.039 and, AMI had a nonsignificant reduction in patients with TTS. CV Re-admission (%) 6.6 18.1 0.58 0.42–0.81 0.001 Although global mortality was 16.1% in non-TTS MINOCAs Global Mortality (%) 8.1 16.1 0.87 0.64–1.19 0.392 and 8.1% in TTS, there were no statistical differences in global Follow-up survival analysis adjusted by propensity score matching with main mortality after PS matching. potential arguments of cardiovascular events (age, hypertension, diabetes, tobacco, Cardiovascular readmissions were higher in non-TTS and dyslipidemia). individuals (HR: 0.58, CI: 0.42–0.81). The time-to-event analysis MINOCAs, myocardial infarction with nonobstructive coronary arteries; MACE, major adverse cardiovascular events (infarction, transient ischemic attack/stroke, is shown in Figure 1 and Table 5. or cardiovascular death); CV, cardiovascular; TIA, transient ischemic attack; HR, hazard ratio. DISCUSSION AF with MINOCAs could be explained as emboli being the The main conclusion of this study, based on large multicenter underlying physiopathological mechanism for the event (1, 4, 5). registries, is that TTS has a different clinical profile than the Another interesting fact is the higher proportion of migraine rest of MINOCAs: (1) TTS affects women at a greater rate; (2) in the group of TTS. Nociceptive mechanisms of migraine are acute phase of TTS is much more aggressive, with worst Killip– thought to be related to vascular tone dysregulation (23), one of Kimball class, more EKG abnormalities, higher levels of cardiac the possible mechanisms that partake in TTS. biomarkers and higher in-hospital mortality; and (3) Long-term The association of psychiatric disorders with TTS is well- cardiovascular prognosis of TTS is better, with less MACE. established (13, 20); these results being consistent with the This study is the first large multicenter study to compare previous literature. In the recent years, TTS physical triggers MINOCAs and non-TTS MINOCAs. The main clinical are acquiring more relevance (24), and this study reflects how implications of these results are its implications on follow-up TTS patients have more extracardiac comorbidities, with lower management after discharge. Once the acute phase has been hemoglobin levels and higher C-reactive protein. The research managed, this article might suggest that patients with TTS of Santoro et al. (25) has already exposed the differences can safely be transferred to the general practitioner, whereas in inflammatory interleukins patter between TTS and acute non-TTS MINOCAs are still at considerable risk of MACE and coronary syndrome. Patients with TTS showed increased levels could benefit from specific follow-up. of anti-inflammatory interleukins during the acute phase. A higher rate of AF in patients with non-TTS MINOCAs is Another key issue is that TTS was an intercurrent remarkable, even when considering they are younger and with complication in hospitalization due to other causes in almost less hypertension than patients with TTS. The association of thirtyfold over patients with non-TTS. Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 March 2022 | Volume 9 | Article 742010 Lopez-Pais et al. Takotsubo Is Not a MINOCA The acute phase of TTS is aggressive compared to non- (30, 31), despite the limitation of lack of randomized control TTS MINOCAs, with twofold in-hospital mortality. As RETAKO trials (first one is currently under recruitment [MINOCAs- investigators have previously described, cardiogenic shock is not BAT: EudraCT number: 2018-000889-11, ClinicalTrials.gov unusual in patients with non-TTS (12%) (26), almost fourfold identifier: NCT03686696]). However, this study reflects that the proportion of cardiogenic shock in non-TTS MINOCAs. in real life, only 58% of the patients were treated according Recently, an interesting score has been proposed to assess the risk to the guidelines. Even lower rates (23.5%) are registered of in-hospital complications on TTS (27). in the non-TTS MINOCAs group for the DAT, despite The significant events during follow-up in the MINOCAs ESC recommendations. group could be due to misdiagnosis at index episode. This Going back to the starting point, it is still unclear how study shows a low use of cardiac magnetic resonance (CMR) clinicians should deal with this disarrayed group of patients. in accordance with Bhatia et al. (28), who proposed that CMR Artificial intelligence is meant to be the next revolution in should be mandatory in every patient with elevated troponin and medicine, but it is also based on proper and precise classifications normal coronary angiography. Recently, the group of Dastidar (32) that need to be reinforced by evidence. has shown the prognostic implications of the use of CMR in this In conclusion, according to this study, TTS shows clear context (29). differences from the rest of the MINOCAs group. TTS Although the pathophysiology of TTS remains unknown, the presents profile of a unique patient, a more aggressive evidence available supports chronic treatment with ACEI/ARB clinical presentation, and worse in-hospital outcomes. However, FIGURE 2 | Takotsubo shows clear differences with patients with MINOCAs, with a unique profile of the patient, a more aggressive acute phase and better long-term cardiovascular prognosis. MINOCAs, myocardial infarction with nonobstructive coronary arteries; TTS, Takotsubo syndrome; MACE, major adverse cardiovascular events (infarction, transient ischemic attack/stroke, or cardiovascular death); CV, cardiovascular; TIA, transient ischemic attack; HR, hazard ratio. Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 March 2022 | Volume 9 | Article 742010 Lopez-Pais et al. Takotsubo Is Not a MINOCA their long-term cardiovascular prognosis is better than non- DATA AVAILABILITY STATEMENT TTS MINOCAs. Based on this, it is congruent to propose that TTS should The original contributions presented in the study are included be considered acute cardiomyopathy. Although it can mimic an in the article/Supplementary Material, further inquiries can be acute coronary syndrome, once the diagnosis of TTS is made, directed to the corresponding author. including it on the working diagnosis MINOCAs do not offer any advantage. This work supports the recent exclusion of TTS ETHICS STATEMENT from MINOCAs. The studies involving human participants were reviewed and Study Limitations approved by Comité Ético de Galicia. The patients/participants Because of its observational nature, unmeasured confounders provided their written informed consent to participate in could constrain causal inference in this study. However, this study. prospective follow-up may allow the application of the causal inference methods. AUTHOR CONTRIBUTIONS As MINOCAs is a syndromic diagnosis rather than a physiopathological one, this could lead to disagreement JL-P and IN-G contributed to the conception or design of the between physicians at the time of considering whether a work and final approval of the version to be published. BI, patient is a MINOCAs or not. This fact is mitigated by SR-R, MA-D, LÁ, OV, AS, AM-G, AU, EB, IM, well-delimiting the inclusion criteria, the thorough review EA-A, DG, MS, ME, and RA-B contributed to the conducted by the authors, and the multicentric nature of data collection. JL-P, MA-D, DL, JG, JA, and IN-G the study. contributed to the data analysis and interpretation. JL-P and BI drafted the article. DL, JG, JA, JG-J, MP, and CONCLUSION IN-G contributed to the critical revision of the article. All authors contributed to the article and approved the submitted version. Takotsubo syndrome has a different clinical profile than the rest of MINOCAs (Figure 2): FUNDING (1) Takotsubo syndrome affects women to a greater extent; they have more psychiatric diseases and less AF. TTS The RETAKO registry was sponsored by the Spanish Society is most frequently an intercurrent complication during of Cardiology. hospitalization for other causes. (2) The acute phase of TTS is much more aggressive, with worst SUPPLEMENTARY MATERIAL Killip–Kimball class, more EKG abnormalities, higher levels of cardiac biomarkers, and higher in-hospital mortality. The Supplementary Material for this article can be found (3) The long-term cardiovascular prognosis of TTS is better, online at: https://www.frontiersin.org/articles/10.3389/fcvm. with less MACE. 2022.742010/full#supplementary-material REFERENCES patients: Clinical features, treatment and 1 year follow-up. Int J Cardiol. (2019) 287:27–31. doi: 10.1016/j.ijcard.2019.02.036 1. 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This is an open-access article distributed under the terms 25. Santoro F, Costantino MD, Guastafierro F, Triggiani G, Ferraretti A, of the Creative Commons Attribution License (CC BY). The use, distribution or Tarantino N, et al. Inflammatory patterns in Takotsubo cardiomyopathy reproduction in other forums is permitted, provided the original author(s) and the and acute coronary syndrome: a propensity score matched analysis. copyright owner(s) are credited and that the original publication in this journal Atherosclerosis. (2018) 274:157–61. doi: 10.1016/j.atherosclerosis.2018. is cited, in accordance with accepted academic practice. No use, distribution or 05.017 reproduction is permitted which does not comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 March 2022 | Volume 9 | Article 742010