IJCA-18021; No of Pages 4 International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Cardiac biomarkers in Takotsubo cardiomyopathy Denis Doyen a,⁎, Pamela Moceri a, Olivier Chiche a, Elie Schouver a, Pierre Cerboni a, Claire Chaussade a, Nicolas Mansencal b, Emile Ferrari a a
Cardiology Department, Pasteur University Hospital, Nice, France Cardiology Department, University Hospital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, UFR de médecine Paris–Ile de France–Ouest, Faculté de Versailles—Saint Quentin en Yveline, Boulogne, France
b
a r t i c l e
i n f o
Article history: Received 5 April 2014 Accepted 9 April 2014 Available online xxxx Keywords: Takotsubo cardiomyopathy Cardiac biomarkers B-type natriuretic peptide Troponin I Acute coronary syndrome
Takotsubo cardiomyopathy (TTC) has recently been identified [1,2]. TTC prevalence is up to 7% of all suspected acute coronary syndromes (ACS) in women, and 1% when both sexes are considered [3,4]. Rehospitalizations are frequent and TTC mortality rate is higher than in the general population [5]. Early phases of TTC mimic ACS and distinguishing one from the other could be tricky [6]. Cardiac biomarkers use would therefore be interesting. However, only few biological data are available [7,8]. We aimed to analyze B-type natriuretic peptide (BNP) and troponin I (TnI) in TTC patients. We conducted a multicentric prospective study between May 2009 and October 2012. We recruited consecutive patients hospitalized for TTC and anterior ACS (age and gender matched) in 3 centers. ACS was diagnosed and treated in accordance with the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association criteria [9–11]. TTC was diagnosed using the Mayo Clinic criteria [6,12]. We conducted this study in compliance with the ethical principles of the Declaration of Helsinki. Approval by the local ethics committee was obtained. Each patient gave his written informed consent. BNP levels were measured on admission. TnI dosage was realized on admission, then every 6 h for 24 h. Three patterns of TnI kinetic were identified: 1) peak (when TnI reaches a maximum before decreasing),
⁎ Corresponding author at: Pasteur University Hospital, Cardiology Department, 30 avenue de la Voie Romaine, 06000, Nice, France. Tel.: +33 678992938; fax: +33 492035607. E-mail address: [email protected] (D. Doyen).
2) decreasing (when TnI decreases continuously after the first assay) and 3) plateau (in the absence of clear peak). BNP/TnI ratio was calculated using the TnI peak value. TnI measurements were performed with the Beckman Access method, with a lowest detection limit of 0.01 ng/ml and a positivity threshold of 0.06 ng/ml. BNP measurements were performed using an immunoassay Beckman Triage method, with a positivity threshold of 100 pg/L. Glomerular filtration rate was evaluated (Modification of Diet in Renal Disease formula). Patients with severe renal failure were excluded (b30 ml/mn). A high risk of bleeding was defined with at least one of the following criteria: symptomatic bleeding, organic lesions likely to bleed, hemostatic abnormalities (platelet count b100,000/mm3, aPTT ratio N2, prothrombin time b40%), or the presence of severe anemia (hemoglobin b8 g/dl) due to bleeding or unexplained. In this study, 62 TTC and 90 ACS patients (47 anterior ST-segment elevation myocardial infarctions (STEMI) and 43 anterior non-STsegment elevation myocardial infarctions (NSTEMI)) were recruited over a 41-month period. The main features of our population are Table 1 Main features of our population. Data are presented as median [interquartile range], or % (n). p Value
Variable
Takotsubo cardiomyopathy (n = 62)
Acute coronary syndromes (n = 90)
Age (years) Gender (women/Men) Smoker Dyslipidemia Diabetes Hypertension Family history of premature coronary heart disease Overweight Previous coronary heart disease Renal dysfunction⁎ Stressful trigger events Physical stress Emotional stress Chest pain Dyspnea Syncope In-hospital mortality
73.5 [64.7–79.4] 85.5%/14.5% (53/9) 45.1% (28) 27.4% (17) 6.5% (4) 48.4% (30) 6.5% (4)
76.0 [66.0–82.0] 85.5%/14.5% (77/13) 40% (36) 46.7% (42) 27.8% (25) 62.2% (56) 4.4% (4)
0.136 0.990 0.526 0.017 0.001 0.091 0.586
16.1% (10) 3.2% (2)
30.0% (27) 19.6% (18)
0.058 0.003
27.4% (17) 82.3% (51) 69.4% (43) 56.5% (35) 48.4% (30) 48.4% (30) 21.0% (13) 1.6% (1)
32.2% (29) 12.2% (11) 10.0% (9) 8.9% (8) 88.9% (80) 23.3% (21) 6.7% (6) 5.6% (5)
0.526 b0.001 b0.001 b0.001 b0.001 0.001 0.010 0.229
⁎Defined as a glomerular filtration rate between 30 and 60 ml/min calculated with the modification of diet in renal disease formula.
http://dx.doi.org/10.1016/j.ijcard.2014.04.120 0167-5273/© 2014 Elsevier Ireland. Ltd
Please cite this article as: Doyen D, et al, Cardiac biomarkers in Takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.04.120
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D. Doyen et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 2 Echocardiogram and electrocardiogram features. Data are presented as median [interquartile range] or as % (n). Variable
TTC (n = 62)
NSTEMI (n = 43)
STEMI (n = 47)
p value TTC vs NSTEMI
LVEF TTC patterns Apical TTC Midventricular TTC Inverted TTC ECG on admission Normal ST segment elevation ST segment depression Inverted T waves Q waves Anterior leads modifications Inverted T waves 24 h after admission
35 [30–40]
45 [35–55]
40 [35–40]
b0.001
p value TTC vs STEMI 0.014
16.3% (7) 0% (0) 44.2% (19) 39.5% (17) 32.5% (14) 83.7% (36) 69.7% (30)
0% (0) 100.0% (47) 55.3% (26) 21.3% (10) 59.6% (28) 100.0% (47) 85.1% (40)
0.687 b0.001 b0.001 0.062 0.632 0.427 b0.001
0.001 b0.001 b0.001 b0.001 0.020 b0.001 0.002
75.8% (47) 22.6% (14) 1.6% (1) 19.0% (12) 53.2% (33) 1.6% (1) 58.0% (36) 37.0% (23) 77.4% (48) 100.0% (62)
ECG: electrocardiogram; LVEF: left ventricular ejection fraction; NSTEMI: non-ST-segment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction; TnI: troponin I; TTC: Takotsubo cardiomyopathy.
Table 3 Biological parameters in patients presenting with Takotsubo cardiomyopathy or acute coronary syndrome. Data are presented as median [interquartile range], or mean (±standard deviation). Variable
TTC (n = 62)
NSTEMI (n = 43)
STEMI (n = 47)
p Value TTC versus NSTEMI
p Value TTC versus STEMI
BNP (pg/L) TnI peak (ng/mL) BNP/TnI (pg/μg) Creatininemia (μmol/L) MDRD clearance (ml/mn) CPK peak (UI/L) CPK-MB peak (UI/L) Myoglobin peak (UI/L) Hemoglobin (g/dL)
972.0 [578.5–1671.0] 1.6 [0.7–3.1] 642.0 [331.8–1226.5] 77.9 (±24.6) 73.0 [58.8–90.3] 193.0 [98.0–307.5] 37.0 [26.5–46.0] 69.5 [50.5–152.5] 13.1 (±1.7)
358.0 [50.5–688.0] 2.1 [0.4–9.4] 184.5 [50.5–372.3] 79.9 (±23.8) 79.0 [54.0–89.0] 199.0 [99.0–390.0] 39.0 [26.5–66.5] 81.0 [35.5–149.0] 12.8 (±2.0)
381.0 [106.0–934.0] 51.4 [27.6–80.1] 7.5 [2.0–29.6] 83.2 (±24.5) 68.0 [53.0–86.0] 1501.0 [1087.0–2851.0] 211.0 [115.0–407.0] 331.0 [188.0–637.0] 13.7 (±1.5)
b0.001 0.319 b0.001 0.683 0.878 0.476 0.171 0.986 0.472
b0.001 b0.001 b0.001 0.275 0.416 b0.001 b0.001 b0.001 0.046
BNP: B-type natriuretic peptide; CPK: creatine phosphokinase; CPK-MB: MB isoenzyme of creatine phosphokinase; MDRD: Modification of Diet in Renal Disease; NSTEMI: non-STsegment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction; TnI: troponin I; TTC: Takotsubo cardiomyopathy.
presented in Table 1. Echocardiogram and electrocardiogram features are presented in Table 2. High-bleeding risk was identified in 37.7%. In TTC, TnI was positive on admission for 98.4%, with a peak occurring earlier compared to overall ACS (6.0 [0.0–12.0] vs 12.0 [6.0–18.0] hours, p b 0.001). TnI levels remain lower than in STEMI, but no different from NSTEMI (Table 3). While TnI “peak profile” was mostly observed, “decreasing profile” was more frequent compared to NSTEMI and STEMI (Fig. 1, Table 4). BNP levels and BNP/TnI ratio were significantly higher in TTC compared to STEMI and NSTEMI (Fig. 2, Table 3). With ST-segment elevation, a single TnI measurement above 5.2 ng/mL could exclude TTC with a 93.6% sensitivity and a 100% specificity (AUC 0.97; p b 0.001) (Fig. 3). A BNP/TnI ratio greater than 159 identified TTC with a 95.2% sensitivity and a 97.9% specificity (AUC 0.98, p b 0.001) (Fig. 4). Without ST-segment elevation, a BNP/TnI ratio greater than 310 excluded ACS with an 82.3% sensitivity and a 71.4% specificity (AUC 0.81, p b 0.001) (Fig. 4). Our study had several implications: first, we showed that BNP levels were higher in patients with TTC compared to those with ACS; but also that troponin levels were lower in comparison to STEMI, but comparable to NSTEMI. Similarly, previous studies on smaller cohorts reported that TTCs are characterized by a greater increase in BNP and less myonecrosis than STEMI [13]. Studying TnI kinetics revealed interesting findings: in TTC, TnI was rarely negative on admission, TnI peak occurred earlier, and “decreasing profile” was more frequent. The early positivity TnI in TTC patients may result from delayed referral to ICU (66.1% of TTC patients were first admitted for another medical reason). The frequent “decreasing profile” is in agreement with this hypothesis, suggesting a putative peak occurring, related to the short duration of the cardiotoxic stress, earlier than admission.
In our study, BNP/TnI ratio was interesting for TTC/ACS discrimination, in particular in patients with ST-segment elevation. To calculate BNP/TnI ratio, we used TnI peak because TnI on admission was not as selective (AUC 0.61; p = 0.023). Previous studies observed higher BNP/troponin T or NT-proBNP/ troponin T ratio in TTC. Our study is the first to investigate TnI kinetics. We compared TTC with anterior ACS patients, as TTC generally concern only anterior leads [14,15].
Fig. 1. Proportion of troponin I kinetic patterns in TTC, NSTEMI and STEMI patients.
Please cite this article as: Doyen D, et al, Cardiac biomarkers in Takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.04.120
D. Doyen et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Table 4 Proportions of TnI kinetic profile for TTC, NSTEMI and STEMI. Data are presented as % (n). TnI profile
TTC (n = 62)
NSTEMI (n = 43)
STEMI (n = 47)
p Value TTC vs NSTEMI
p Value TTC vs STEMI
Peak profile Decreasing profile Plateau profile
61.0% (36) 28.8% (17) 10.2% (6)
71.4% (30) 9.5% (4) 19.0% (8)
75.6% (34) 2.2% (1) 22.2% (10)
0.278 0.019 0.203
0.117 b0.001 0.091
NSTEMI: non-ST-segment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction; TnI: troponin I; TTC: Takotsubo cardiomyopathy.
Clearly, current cardiac biomarkers are not specific enough to definitely differentiate between TTC from ACS. However, evaluating their levels could help in distinguishing TTC from ACS, especially when coronary angiogram and echocardiography are discordant, in particular when a significant coronary artery lesion does not explain the wall motion abnormalities. A score combining clinical history, electrocardiographic analysis, echocardiographic data and cardiac biomarkers would be interesting to cut short the issue. We studied a relatively small number of TTC patients. However, this is to date the largest cohort study investigating cardiac biomarkers in TTC. BNP was preferred over NT-proBNP, since it is less dependent on renal function. In addition, BNP is often the only peptide assay available in the emergency room. In conclusion, BNP and TnI have a particular biological profile in TTC patients, further characterizing this syndrome. In tricky situations, especially when coronary angiogram is difficult to obtain in patients who are at high risk of bleeding, cardiac biomarkers might be helpful to identify TTC and avoid useless antithrombotic therapy. Fig. 2. Box plots representing BNP/TnI ratio in TTC, NSTEMI and STEMI patients; BNP/TnI ratio is higher in TTC than in NSTEMI and STEMI patients (642.0 [331.8–1226.5] versus 184.5 [50.5–372.3] and 7.5 [2.0–29.6]; p b 0.001 and p b 0.001 respectively).
Coronary angiogram is the main exam that will ultimately discriminate TTC from ACS. However, distinguishing TTC from ACS is of major concern in some high-risk bleeding patients, especially when coronary angiogram is difficult to perform in emergency (24.2% of our patients hospitalized in intensive care unit were unable to undergo emergency coronary angiography).
Fig. 3. Receiver operating characteristic curve for TnI peak values in patients with ST-segment elevation. TnI peak can distinguish STEMI patients from TTC patients (cut-off: 5.18; area under ROC curve of 0.97 [0.91–0.99], p b 0.001).
Acknowledgments The authors would like to thank Dr François Bernasconi (Department of Cardiology, La Fontonne Hospital, Antibes, France) and Dr Thierry Tibi (Department of Cardiology, Les Broussailles Hospital, Cannes, France) for their participation in the study. References [1] Satoh H, TH UT. Takotsubo type cardiomyopathy due to multivessel spasm. Clinical aspect of myocardial injury: from ischemia to heart failure; 1990 56–64. [2] Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991;21:203–14. [3] Wedekind H, Moller K, Scholz KH. Takotsubo cardiomyopathy. Incidence in patients with acute coronary syndrome. Herz 2006;31:339–46. [4] Mansencal N, Auvert B, N'Guetta R, et al. Prospective assessment of incidence of Tako-Tsubo cardiomyopathy in a very large urban agglomeration. Int J Cardiol 2013;168:4536–8. [5] Parodi G, Bellandi B, Del Pace S, et al. Natural history of tako-tsubo cardiomyopathy. Chest 2011;139:887–92. [6] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. [7] Frohlich GM, Schoch B, Schmid F, et al. Takotsubo cardiomyopathy has a unique cardiac biomarker profile: NT-proBNP/myoglobin and NT-proBNP/troponin T ratios for the differential diagnosis of acute coronary syndromes and stress induced cardiomyopathy. Int J Cardiol 2012;154:328–32. [8] Ahmed KA, Madhavan M, Prasad A. Brain natriuretic peptide in apical ballooning syndrome (Takotsubo/stress cardiomyopathy): comparison with acute myocardial infarction. Coron Artery Dis 2012;23:259–64. [9] Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. [10] Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054. [11] Wright RS, Anderson JL, Adams CD, et al. ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;57:1920–59.
Please cite this article as: Doyen D, et al, Cardiac biomarkers in Takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.04.120
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Fig. 4. Receiver operating characteristic curves for BNP/TnI ratio in patients with ST-segment elevation (4a) and without ST-segment elevation (4b); area under ROC curve of 0.98 ([0.94–0.99], p b 0.001) and 0.81 ([0.72–0.88], p b 0.001), respectively in patients with and without ST-segment elevation. [12] Madhavan M, Prasad A. Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo cardiomyopathy and long-term prognosis. Herz 2010;35:240–3. [13] Madhavan M, Borlaug BA, Lerman A, Rihal CS, Prasad A. Stress hormone and circulating biomarker profile of apical ballooning syndrome (Takotsubo cardiomyopathy): insights into the clinical significance of B-type natriuretic peptide and troponin levels. Heart 2009;95:1436–41.
[14] Dib C, Asirvatham S, Elesber A, Rihal C, Friedman P, Prasad A. Clinical correlates and prognostic significance of electrocardiographic abnormalities in apical ballooning syndrome (Takotsubo/stress-induced cardiomyopathy). Am Heart J 2009;157:933–8. [15] Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol 2008;124:283–92.
Please cite this article as: Doyen D, et al, Cardiac biomarkers in Takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.04.120
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Cardiac biomarkers in Takotsubo cardiomyopathy Denis Doyen a,⁎, Pamela Moceri a, Olivier Chiche a, Elie Schouver a, Pierre Cerboni a, Claire Chaussade a, Nicolas Mansencal b, Emile Ferrari a a
Cardiology Department, Pasteur University Hospital, Nice, France Cardiology Department, University Hospital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, UFR de médecine Paris–Ile de France–Ouest, Faculté de Versailles—Saint Quentin en Yveline, Boulogne, France
b
a r t i c l e
i n f o
Article history: Received 5 April 2014 Accepted 9 April 2014 Available online xxxx Keywords: Takotsubo cardiomyopathy Cardiac biomarkers B-type natriuretic peptide Troponin I Acute coronary syndrome
Takotsubo cardiomyopathy (TTC) has recently been identified [1,2]. TTC prevalence is up to 7% of all suspected acute coronary syndromes (ACS) in women, and 1% when both sexes are considered [3,4]. Rehospitalizations are frequent and TTC mortality rate is higher than in the general population [5]. Early phases of TTC mimic ACS and distinguishing one from the other could be tricky [6]. Cardiac biomarkers use would therefore be interesting. However, only few biological data are available [7,8]. We aimed to analyze B-type natriuretic peptide (BNP) and troponin I (TnI) in TTC patients. We conducted a multicentric prospective study between May 2009 and October 2012. We recruited consecutive patients hospitalized for TTC and anterior ACS (age and gender matched) in 3 centers. ACS was diagnosed and treated in accordance with the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association criteria [9–11]. TTC was diagnosed using the Mayo Clinic criteria [6,12]. We conducted this study in compliance with the ethical principles of the Declaration of Helsinki. Approval by the local ethics committee was obtained. Each patient gave his written informed consent. BNP levels were measured on admission. TnI dosage was realized on admission, then every 6 h for 24 h. Three patterns of TnI kinetic were identified: 1) peak (when TnI reaches a maximum before decreasing),
⁎ Corresponding author at: Pasteur University Hospital, Cardiology Department, 30 avenue de la Voie Romaine, 06000, Nice, France. Tel.: +33 678992938; fax: +33 492035607. E-mail address: [email protected] (D. Doyen).
2) decreasing (when TnI decreases continuously after the first assay) and 3) plateau (in the absence of clear peak). BNP/TnI ratio was calculated using the TnI peak value. TnI measurements were performed with the Beckman Access method, with a lowest detection limit of 0.01 ng/ml and a positivity threshold of 0.06 ng/ml. BNP measurements were performed using an immunoassay Beckman Triage method, with a positivity threshold of 100 pg/L. Glomerular filtration rate was evaluated (Modification of Diet in Renal Disease formula). Patients with severe renal failure were excluded (b30 ml/mn). A high risk of bleeding was defined with at least one of the following criteria: symptomatic bleeding, organic lesions likely to bleed, hemostatic abnormalities (platelet count b100,000/mm3, aPTT ratio N2, prothrombin time b40%), or the presence of severe anemia (hemoglobin b8 g/dl) due to bleeding or unexplained. In this study, 62 TTC and 90 ACS patients (47 anterior ST-segment elevation myocardial infarctions (STEMI) and 43 anterior non-STsegment elevation myocardial infarctions (NSTEMI)) were recruited over a 41-month period. The main features of our population are Table 1 Main features of our population. Data are presented as median [interquartile range], or % (n). p Value
Variable
Takotsubo cardiomyopathy (n = 62)
Acute coronary syndromes (n = 90)
Age (years) Gender (women/Men) Smoker Dyslipidemia Diabetes Hypertension Family history of premature coronary heart disease Overweight Previous coronary heart disease Renal dysfunction⁎ Stressful trigger events Physical stress Emotional stress Chest pain Dyspnea Syncope In-hospital mortality
73.5 [64.7–79.4] 85.5%/14.5% (53/9) 45.1% (28) 27.4% (17) 6.5% (4) 48.4% (30) 6.5% (4)
76.0 [66.0–82.0] 85.5%/14.5% (77/13) 40% (36) 46.7% (42) 27.8% (25) 62.2% (56) 4.4% (4)
0.136 0.990 0.526 0.017 0.001 0.091 0.586
16.1% (10) 3.2% (2)
30.0% (27) 19.6% (18)
0.058 0.003
27.4% (17) 82.3% (51) 69.4% (43) 56.5% (35) 48.4% (30) 48.4% (30) 21.0% (13) 1.6% (1)
32.2% (29) 12.2% (11) 10.0% (9) 8.9% (8) 88.9% (80) 23.3% (21) 6.7% (6) 5.6% (5)
0.526 b0.001 b0.001 b0.001 b0.001 0.001 0.010 0.229
⁎Defined as a glomerular filtration rate between 30 and 60 ml/min calculated with the modification of diet in renal disease formula.
http://dx.doi.org/10.1016/j.ijcard.2014.04.120 0167-5273/© 2014 Elsevier Ireland. Ltd
Please cite this article as: Doyen D, et al, Cardiac biomarkers in Takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.04.120
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D. Doyen et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 2 Echocardiogram and electrocardiogram features. Data are presented as median [interquartile range] or as % (n). Variable
TTC (n = 62)
NSTEMI (n = 43)
STEMI (n = 47)
p value TTC vs NSTEMI
LVEF TTC patterns Apical TTC Midventricular TTC Inverted TTC ECG on admission Normal ST segment elevation ST segment depression Inverted T waves Q waves Anterior leads modifications Inverted T waves 24 h after admission
35 [30–40]
45 [35–55]
40 [35–40]
b0.001
p value TTC vs STEMI 0.014
16.3% (7) 0% (0) 44.2% (19) 39.5% (17) 32.5% (14) 83.7% (36) 69.7% (30)
0% (0) 100.0% (47) 55.3% (26) 21.3% (10) 59.6% (28) 100.0% (47) 85.1% (40)
0.687 b0.001 b0.001 0.062 0.632 0.427 b0.001
0.001 b0.001 b0.001 b0.001 0.020 b0.001 0.002
75.8% (47) 22.6% (14) 1.6% (1) 19.0% (12) 53.2% (33) 1.6% (1) 58.0% (36) 37.0% (23) 77.4% (48) 100.0% (62)
ECG: electrocardiogram; LVEF: left ventricular ejection fraction; NSTEMI: non-ST-segment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction; TnI: troponin I; TTC: Takotsubo cardiomyopathy.
Table 3 Biological parameters in patients presenting with Takotsubo cardiomyopathy or acute coronary syndrome. Data are presented as median [interquartile range], or mean (±standard deviation). Variable
TTC (n = 62)
NSTEMI (n = 43)
STEMI (n = 47)
p Value TTC versus NSTEMI
p Value TTC versus STEMI
BNP (pg/L) TnI peak (ng/mL) BNP/TnI (pg/μg) Creatininemia (μmol/L) MDRD clearance (ml/mn) CPK peak (UI/L) CPK-MB peak (UI/L) Myoglobin peak (UI/L) Hemoglobin (g/dL)
972.0 [578.5–1671.0] 1.6 [0.7–3.1] 642.0 [331.8–1226.5] 77.9 (±24.6) 73.0 [58.8–90.3] 193.0 [98.0–307.5] 37.0 [26.5–46.0] 69.5 [50.5–152.5] 13.1 (±1.7)
358.0 [50.5–688.0] 2.1 [0.4–9.4] 184.5 [50.5–372.3] 79.9 (±23.8) 79.0 [54.0–89.0] 199.0 [99.0–390.0] 39.0 [26.5–66.5] 81.0 [35.5–149.0] 12.8 (±2.0)
381.0 [106.0–934.0] 51.4 [27.6–80.1] 7.5 [2.0–29.6] 83.2 (±24.5) 68.0 [53.0–86.0] 1501.0 [1087.0–2851.0] 211.0 [115.0–407.0] 331.0 [188.0–637.0] 13.7 (±1.5)
b0.001 0.319 b0.001 0.683 0.878 0.476 0.171 0.986 0.472
b0.001 b0.001 b0.001 0.275 0.416 b0.001 b0.001 b0.001 0.046
BNP: B-type natriuretic peptide; CPK: creatine phosphokinase; CPK-MB: MB isoenzyme of creatine phosphokinase; MDRD: Modification of Diet in Renal Disease; NSTEMI: non-STsegment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction; TnI: troponin I; TTC: Takotsubo cardiomyopathy.
presented in Table 1. Echocardiogram and electrocardiogram features are presented in Table 2. High-bleeding risk was identified in 37.7%. In TTC, TnI was positive on admission for 98.4%, with a peak occurring earlier compared to overall ACS (6.0 [0.0–12.0] vs 12.0 [6.0–18.0] hours, p b 0.001). TnI levels remain lower than in STEMI, but no different from NSTEMI (Table 3). While TnI “peak profile” was mostly observed, “decreasing profile” was more frequent compared to NSTEMI and STEMI (Fig. 1, Table 4). BNP levels and BNP/TnI ratio were significantly higher in TTC compared to STEMI and NSTEMI (Fig. 2, Table 3). With ST-segment elevation, a single TnI measurement above 5.2 ng/mL could exclude TTC with a 93.6% sensitivity and a 100% specificity (AUC 0.97; p b 0.001) (Fig. 3). A BNP/TnI ratio greater than 159 identified TTC with a 95.2% sensitivity and a 97.9% specificity (AUC 0.98, p b 0.001) (Fig. 4). Without ST-segment elevation, a BNP/TnI ratio greater than 310 excluded ACS with an 82.3% sensitivity and a 71.4% specificity (AUC 0.81, p b 0.001) (Fig. 4). Our study had several implications: first, we showed that BNP levels were higher in patients with TTC compared to those with ACS; but also that troponin levels were lower in comparison to STEMI, but comparable to NSTEMI. Similarly, previous studies on smaller cohorts reported that TTCs are characterized by a greater increase in BNP and less myonecrosis than STEMI [13]. Studying TnI kinetics revealed interesting findings: in TTC, TnI was rarely negative on admission, TnI peak occurred earlier, and “decreasing profile” was more frequent. The early positivity TnI in TTC patients may result from delayed referral to ICU (66.1% of TTC patients were first admitted for another medical reason). The frequent “decreasing profile” is in agreement with this hypothesis, suggesting a putative peak occurring, related to the short duration of the cardiotoxic stress, earlier than admission.
In our study, BNP/TnI ratio was interesting for TTC/ACS discrimination, in particular in patients with ST-segment elevation. To calculate BNP/TnI ratio, we used TnI peak because TnI on admission was not as selective (AUC 0.61; p = 0.023). Previous studies observed higher BNP/troponin T or NT-proBNP/ troponin T ratio in TTC. Our study is the first to investigate TnI kinetics. We compared TTC with anterior ACS patients, as TTC generally concern only anterior leads [14,15].
Fig. 1. Proportion of troponin I kinetic patterns in TTC, NSTEMI and STEMI patients.
Please cite this article as: Doyen D, et al, Cardiac biomarkers in Takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.04.120
D. Doyen et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Table 4 Proportions of TnI kinetic profile for TTC, NSTEMI and STEMI. Data are presented as % (n). TnI profile
TTC (n = 62)
NSTEMI (n = 43)
STEMI (n = 47)
p Value TTC vs NSTEMI
p Value TTC vs STEMI
Peak profile Decreasing profile Plateau profile
61.0% (36) 28.8% (17) 10.2% (6)
71.4% (30) 9.5% (4) 19.0% (8)
75.6% (34) 2.2% (1) 22.2% (10)
0.278 0.019 0.203
0.117 b0.001 0.091
NSTEMI: non-ST-segment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction; TnI: troponin I; TTC: Takotsubo cardiomyopathy.
Clearly, current cardiac biomarkers are not specific enough to definitely differentiate between TTC from ACS. However, evaluating their levels could help in distinguishing TTC from ACS, especially when coronary angiogram and echocardiography are discordant, in particular when a significant coronary artery lesion does not explain the wall motion abnormalities. A score combining clinical history, electrocardiographic analysis, echocardiographic data and cardiac biomarkers would be interesting to cut short the issue. We studied a relatively small number of TTC patients. However, this is to date the largest cohort study investigating cardiac biomarkers in TTC. BNP was preferred over NT-proBNP, since it is less dependent on renal function. In addition, BNP is often the only peptide assay available in the emergency room. In conclusion, BNP and TnI have a particular biological profile in TTC patients, further characterizing this syndrome. In tricky situations, especially when coronary angiogram is difficult to obtain in patients who are at high risk of bleeding, cardiac biomarkers might be helpful to identify TTC and avoid useless antithrombotic therapy. Fig. 2. Box plots representing BNP/TnI ratio in TTC, NSTEMI and STEMI patients; BNP/TnI ratio is higher in TTC than in NSTEMI and STEMI patients (642.0 [331.8–1226.5] versus 184.5 [50.5–372.3] and 7.5 [2.0–29.6]; p b 0.001 and p b 0.001 respectively).
Coronary angiogram is the main exam that will ultimately discriminate TTC from ACS. However, distinguishing TTC from ACS is of major concern in some high-risk bleeding patients, especially when coronary angiogram is difficult to perform in emergency (24.2% of our patients hospitalized in intensive care unit were unable to undergo emergency coronary angiography).
Fig. 3. Receiver operating characteristic curve for TnI peak values in patients with ST-segment elevation. TnI peak can distinguish STEMI patients from TTC patients (cut-off: 5.18; area under ROC curve of 0.97 [0.91–0.99], p b 0.001).
Acknowledgments The authors would like to thank Dr François Bernasconi (Department of Cardiology, La Fontonne Hospital, Antibes, France) and Dr Thierry Tibi (Department of Cardiology, Les Broussailles Hospital, Cannes, France) for their participation in the study. References [1] Satoh H, TH UT. Takotsubo type cardiomyopathy due to multivessel spasm. Clinical aspect of myocardial injury: from ischemia to heart failure; 1990 56–64. [2] Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991;21:203–14. [3] Wedekind H, Moller K, Scholz KH. Takotsubo cardiomyopathy. Incidence in patients with acute coronary syndrome. Herz 2006;31:339–46. [4] Mansencal N, Auvert B, N'Guetta R, et al. Prospective assessment of incidence of Tako-Tsubo cardiomyopathy in a very large urban agglomeration. Int J Cardiol 2013;168:4536–8. [5] Parodi G, Bellandi B, Del Pace S, et al. Natural history of tako-tsubo cardiomyopathy. Chest 2011;139:887–92. [6] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. [7] Frohlich GM, Schoch B, Schmid F, et al. Takotsubo cardiomyopathy has a unique cardiac biomarker profile: NT-proBNP/myoglobin and NT-proBNP/troponin T ratios for the differential diagnosis of acute coronary syndromes and stress induced cardiomyopathy. Int J Cardiol 2012;154:328–32. [8] Ahmed KA, Madhavan M, Prasad A. Brain natriuretic peptide in apical ballooning syndrome (Takotsubo/stress cardiomyopathy): comparison with acute myocardial infarction. Coron Artery Dis 2012;23:259–64. [9] Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. [10] Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054. [11] Wright RS, Anderson JL, Adams CD, et al. ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;57:1920–59.
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Fig. 4. Receiver operating characteristic curves for BNP/TnI ratio in patients with ST-segment elevation (4a) and without ST-segment elevation (4b); area under ROC curve of 0.98 ([0.94–0.99], p b 0.001) and 0.81 ([0.72–0.88], p b 0.001), respectively in patients with and without ST-segment elevation. [12] Madhavan M, Prasad A. Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo cardiomyopathy and long-term prognosis. Herz 2010;35:240–3. [13] Madhavan M, Borlaug BA, Lerman A, Rihal CS, Prasad A. Stress hormone and circulating biomarker profile of apical ballooning syndrome (Takotsubo cardiomyopathy): insights into the clinical significance of B-type natriuretic peptide and troponin levels. Heart 2009;95:1436–41.
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Please cite this article as: Doyen D, et al, Cardiac biomarkers in Takotsubo cardiomyopathy, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.04.120
