https://orcid.org/0000-0003-3089-1222
Introduction
Takotsubo syndrome (TTS) is characterized by transient left ventricular wall motion anomalies associated with coronary microvascular dysfunction in the absence of culprit lesions of epicardial coronary arteries.1 The clinical presentation of TTS resembles that of typical acute coronary syndrome (ACS).2 Despite coronary angiography being the gold standard for TTS diagnosis, its limitations and unessential role in disease management necessitate non-invasive diagnostic methods.2 Patients with TTS exhibit distinctive patterns of classic cardiac biomarkers compared to patients with ACS. Specifically, TTS is associated with higher brain natriuretic peptide (BNP) levels attributed to heightened filling pressures, and conversely, lower levels of troponin or creatine kinase (CK), as a consequence of distinct pathophysiological mechanisms.2,3 These variations in biomarker levels have been proposed as valuable indicators in differentiating these two entities from another.4 However, although previously proposed ratios of classic cardiac biomarkers exhibit promise in distinguishing TTS from ACS, their applicability was restricted by small sample sizes and a lack of validation.5–9 Thus, the present study aims to validate these ratios in the largest database dedicated to TTS worldwide, the International Takotsubo (InterTAK) Registry.1
Methods
Study population
The InterTAK Registry is an international retrospective and prospective registry for patients with TTS established at the University Hospital of Zurich.1 For inclusion in the study, patients had to meet the criterion of having BNP and troponin taken upon admission prior to undergoing coronary angiography. Peak values were also recorded, if available (n TTS: Troponinpeak: n = 778, CKpeak: n = 687, BNPpeak: n = 758; ACS: Troponinpeak: n = 2355, CKpeak: n = 1621, BNPpeak: n = 1591). The control group consists of consecutive patients with type I myocardial infarction recruited from the Zurich ACS Registry and from five centres included in the Coralys registry, located in Italy, Spain, and Poland.10
Biomarker ratios
Previously proposed ratios for differentiating TTS from ACS derived from biomarkers established in the diagnostic work-up of ACS (troponin, BNP, CK), as well as a formerly proposed score: exp(a)/(1 + exp(a)), a = (−0.031 + 0.013 ∗ age + 0.0003 ∗ (BNPadm/Troponinadm) − 0.077 ∗ LVEF + 2.71 ∗ sex − 2.77 ∗ psychiatric comorbidity, were computed and analysed for their diagnostic accuracy. To handle distinct troponin types, biomarkers were expressed as their upper limit of normal (ULN). All previously published biomarker ratios derived from classic cardiac biomarkers reported to distinguish between ACS and TTS with an area under the receiver-operating characteristic (ROC) curve (AUC) above 0.8 were tested.5–9
Statistical analysis
Continuous variables are given as mean ± standard deviation or median with interquartile range and were tested for differences with the Student’s t-test or Mann–Whitney U test, respectively. Categorical variables are summarized as frequencies and percentages and were analysed using Pearson’s χ2 test or Fisher’s exact test. ROC curves were compiled, and the diagnostic accuracies of proposed biomarker ratios (AUC, sensitivity and specificity at optimal threshold and sensitivity at 90% specificity) were assessed using the pROC function in R Version 4.1. A specificity level of 90% was deemed appropriate, given that erroneously suspecting TTS carries more serious consequences than mistakenly suspecting ACS. A two-sided P-value < .05 was considered statistically significant. R version 4.1 was used for the statistical analysis and compilation of graphs.
Results
Baseline characteristics
The total study cohort consisted of 1060 patients with TTS and 2435 all-comer patients with either ST-elevation myocardial infarction (49.2%) or non-ST-elevation myocardial infarction (50.8%). Patients with TTS were older (68.9 ± 12.5 vs. 66.4 ± 13.2; P < .001) and had a higher prevalence of female sex (84.3% vs. 18.6%, P < .001). Cardiovascular risk factors and clinical variables were distributed significantly different between TTS and ACS patients: hypertension: 63.5% vs. 60.9%; P = .184, diabetes: 15.1% vs. 28.2% (P < .001), dyslipidaemia: 33.4% vs. 48.3% (P < .001), estimated glomerular filtration rate < 35 mL/min: 12.0% vs. 18.8% (P < .001), left ventricular ejection fraction: 39.4% vs. 44.4% (P < .001), and ST-elevation: 39.8% vs. 49.2% (P < .001).
Levels of classic cardiac biomarkers
Patients with TTS exhibited comparable admission troponin values (13.5 [4.0–35.7] vs. 11.6 [2.5–50.5], P = .398), but lower peak troponin values (22.7 [8.9–55.2] vs. 82.9 [12.6–532.0], P < .001). Admission and peak BNP levels were significantly higher in TTS compared to ACS patients (7.2 [2.1–19.8] vs. 2.7 [0.7–10.4] and 10.6 [4.3–27.1] vs. 5.0 [1.6–15.1], both P < .001). CK levels on admission were comparable between the two groups (0.9 [0.5–1.8] vs. 1.0 [0.6, 2.1], P = .394), but at peak significantly higher in patients with ACS (1.2 [0.7, 2.7] vs. 3.2 [1.1, 8.6], P < .001).
Validation of proposed biomarker ratios in an all-comer cohort of acute coronary syndrome and Takotsubo syndrome patients
The performance of previously published biomarker scores in an all-comer cohort of TTS and ACS patients is illustrated in Figure 1.
Formerly proposed biomarker ratios for the differentiation of TTS from ACS. AUC, area under the receiver-operating characteristic curve; diagnostic score: exp(a)/(1 + exp(a)), a = (−0.031 + 0.013 ∗ age + 0.0003 ∗ (BNPadm/Tnadm) − 0.077 ∗ LVEF + 2.71 ∗ (female sex) − 2.77 ∗ (psychiatric comorbidity); BNP, brain natriuretic peptide; Tn, troponin; CK, creatine kinase; LVEF, left ventricular ejection fraction
The diagnostic score derived by Dagrenat et al. showed the highest discriminative ability between ACS and TTS with an AUC of 0.81 (54.3% sensitivity at 90% specificity). The BNP/Troponin ratio at admission exhibited an AUC of 0.62 (9.8% sensitivity at 90% specificity), while the BNP/Troponin ratio at peak only achieved an AUC of 0.70 (25.9% sensitivity at 90% specificity).
The ratio of BNP/CK achieved AUCs of 0.66 (28.8% sensitivity at 90% specificity) for admission values and 0.73 (35.5% sensitivity at 90% specificity) for peak values, respectively.
The Troponin/CK ratios demonstrated lower AUC values, with 0.51 at admission and 0.50 at peak (sensitivity 3.2% and 13.2%, respectively, at 90% specificity).
Discussion
In this study, involving patients from the world’s largest cohort of TTS patients, the efficacy of biomarker ratios in distinguishing TTS from ACS was found to be only moderately successful, with AUC values ranging from 0.5 to 0.8. Despite previous claims that these ratios could accurately differentiate between TTS and ACS, the originally anticipated excellent diagnostic accuracies could not be replicated in our international cohort of TTS patients. Although peak value ratios offer better distinction, the application of peak values in diagnostic ratios for cases with elevated ST-segments poses challenges, as immediate treatment is mandatory. Moreover, the integration of clinical variables and biomarkers holds significant promise for differentiating between the two entities with a higher level of diagnostic accuracy. The variability in the timing of blood collection across different centres for assessment of peak values should be acknowledged as a limitation of a large registry investigating a condition with low incidence, such as the InterTAK. However, measurement of admission values was performed according to international guidelines for the management of ACS.
In conclusion, our study highlights the critical necessity for discovering novel biomarkers to enhance the diagnosis of TTS.
Declarations
Disclosure of Interest
Ch.T. has received institutional grants from Abbott Vascular, Medtronic, and SMT as well as consulting grants from Biotronik, Microport, and Innova. K.E.J.A. received grants or has contracts with the Finnish Foundation for Cardiovascular Research, and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Pfizer, Boerhinger-Ingelheim, and AstraZeneca. J.B. received grants or has contracts with Abiomed, CVRx, Norgine, Roche, and Zoll and holds Patents PCT/EP2007/008772 and PCT/EP2009/051986 for microRNA and downstream targets for diagnostics and therapeutic purposes. Moreover, J.B. received consulting fees from Amgen, Astra Zeneca, Bayer, BMS, Boehringer Ingelheim, Cardior, Corvia, CVRx, Edwards, Norgine, Novartis, Pfizer, Roche, and Vifor and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Astra Zeneca, Bayer, BMS, Boehringer ingelheim, Cardior, CVRx, Norgine, Novartis, Pfizer, and Vifor. Mi.B. received grants or has contracts with Deutsche Forschungsgemeinschaft research support (DFG, SFB-TTR 219, S-01). Moreover, Mi.B. received speaker honoraria from Abbott, Amgen, Astra Zeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, Servier, and Vifor, and is in the advisory board of Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Pfizer, ReCor, Servier, and Vifor. P.C.-F. received payments for lectures, presentations, speakers bureaus, manuscript writing, or educational events from A Menarini, Medinfar, Bayer, AstraZeneca, Biotronik, and Medtronic. Moreover, he received payments for participation on a data safety monitoring board or advisory board from Medtronic. W.D. received consulting fees from Reata. C.K. received consulting fees from the Swiss Federal Office of Public Health, and support for attending meetings and/or travel from Medtronic, Abbott, and Europa Organization. R.K. received institutional grants on behalf of the Luzerner Kantonsspital from Biosense-Webster, Boston, Biotronik, Medtronik, and Sis-Medical, as well as consulting fees from Biosense Webster, Biotronik, and Medtronic. Wo.K. received grants and provision of reagents to institution from Singulex, Dr. Beckmann Pharma, Abott, and Roche Diagnostics and received consulting fees from, AstraZeneca, Novartis, Amgen, Pfizer, The Medicines Company, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, OMEICOS, Daichii Sankyo, Novo Nordisk, New Amsterdam Pharma, TenSixteen Bio, Esperion, and Genentech. Moreover, Wo.K. received lecture fees from BristolMyers Squibb, Novartis, Amgen, Berlin-Chemie, Sanofi, and AstraZeneca. T.F.L. received research or educational grants to the institution from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Novartis, Novo Nordisk, Sanofi, and Vifor and is the president elect of the European Society of Cardiology, chairman of the research committee of the Swiss Heart Foundation, President of the Board of the Zurich Heart House, and Trustee of the London Heart House. Mah.K. received grants or has contracts with Vifor Pharma and Daiichi Sankyo and received consulting fees or payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Vifor, Pharmacosmos, and Sphingotec. Moreover, Mah.K. received equipment, materials, drugs, medical writing, gifts, or other services from Sphingotec and Vifor Pharma. D.N. received consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Gerson Lehmann Group (GLG) Consulting, Novo Nordisk, Pfizer, and Zoll, as well as payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, and Pfizer. Moreover, D.N. received support for attending meetings and/or travel from Abbott, Amgen, Bayer, and Novo Nordisk. M.R. received institutional research grants from Boston Scientific, Cordis, Terumo, Biotronic, and Medtronic. F.R. has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years, the Department of Cardiology (University Hospital of Zurich/University of Zurich), however, reports research-, educational-, and/or travel grants from Abbott, Abiomed, Alexion, Amgen, Astra Zeneca, At the Limits Ltd., Bayer, Berlin Heart, B. Braun, Biosense Webster, Biosensors Europe AG, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, Cardinal Health Switzerland, Concept Medical, Corteria, CSL, Daiichi Sankyo, Diatools AG, Edwards Lifesciences, Guidant Europe NV (BS), Hamilton Health Sciences, IHF, Innosuisse, Johnson/Johnson, Kaneka Corporation, Kantar, Kiniksa, Labormedizinisches Zentrum, MedAlliance, Medical Education Global Solutions, Medtronic, MicroPort, MSD, Mundipharma Medical Company, Novartis, Novo Nordisk, Orion, Pfizer, Quintiles Switzerland Sarl, RecorMedical, Roche Diagnostics, Roche Pharma, Sahajanand IN, Sanofi, Sarstedt AG, Servier, SIS Medical, Sorin CRM SAS, SSS International Clinical Research, Stromal, Terumo Deutschland, Trama Solutions, V-Wave, Vascular Medical, Vifor, Wissens Plus, and ZOLL. F.R. has not received personal payments by pharmaceutical companies or devicemanufacturers in the last 3 years. Remuneration for the time spent in following consulting activities was made directly to the University of Zurich and does not impact on F.R.’s personal remuneration: AstraZeneca (IMC), Bayer, Boehringer Ingelheim, Citi Research, Klub Class, Novo Nordisk, Radcliffe Group, Stiftung Pfizer Forschungspreis, and Vifor. F.R. has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years. Remuneration for following lectures was made directly to the University of Zurich and does not impact on F.R.’s personal remuneration: Abbott, Amgen, AstraZeneca (A+ Science AB), Bayer (At the Limits), Boehringer Ingelheim, Boston Scientific (CCE Services), Brigham and Women’s Hospital Boston, C.T.I GmbH, FomF, Hôpitaux Universitaires des Genève (GECORE), Luzerner Kantonsspital, Sanofi-Aventis, Servier, Medcon, Medscape (WebMD), Medtronic, Medworld, Novartis, Roche, Ruwag, Swiss Heart Failure Academy, The Hong Kong Heart Failure Society, Trama Solutions SL, Inselspital Bern, Charité—Universitätsmedizin Berlin (Medical Education Global Solutions), Romanian Society of Cardiology, ÖKG Österreichische Gesellschaft für Kardiologie, and Zoll. F.R. received support for attending meetings and/or travel from AstraZeneca (IMC/A+ Science AB), Boehringer Ingelheim, Centro Hospitaler de Vila Nova de Gaia, C.T.I. GmbH (Universitätsklinikum Düsseldorf), European Society of Cardiology, Monocle, Novartis, Spektar Putovanja, Austrian Heart Failure Association, and Heart Failure Association of the ESC. F.R. has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years. Remuneration for following advisory boards was made directly to the University of Zurich and does not impact on F.R.’s personal remuneration: Bayer, Roche, IMC/AstraZeneca, and Amgen. F.R. moreover received secretarial and administrative support of the HFA for his role as President/Past-President 2018–20. H.S. received consulting fees from Amgen, Daiichi-Sankyo, MSD Sharp&Dohme, AstraZeneca, Bayer, Boerhinger Ingelheim, Novartis, and Servier, as well as honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and support for attending meetings and/or travel from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BristolMyers Squibb, Daiichi Sankyo, MSD Sharp&Dohme, Novartis, Sanofi Aventis, Servier, and Synlab. H.S. further received honoraria for his participation on a data safety monitoring board or advisory board of Boehringer Ingelheim, Daiichi-Sankyo, Novartis, and Amgen. Ma.W. received consulting fees from NVT/Biosensors as well as payments for lectures, presentations, speakers bureaus, manuscript writing, or educational events from NVT/Biosensors. Moreover, Ma.W. has Equities in Hi-D Imaging, Winterthur, Switzerland. Fi.C. received personal fees from Amgen, Astra Zeneca, Abbott, Menarini, Chiesi, and Daiichi Sankyo, outside the submitted work. The remaining authors have nothing to disclose.
Data Availability
Data might be made available after inquiry.
Funding
All authors declare no funding for this contribution.
Ethical Approval
Ethical approval has been obtained for this study from the local ethics committee [Kantonale Ethikkommission Zürich (KEK) BASEC-ID: ID PB_2017-00279].
Pre-registered Clinical Trial Number
The pre-registered clinical trial number is NCT01947621.
