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Multicenter Study
. 2021 Jul 1;6(7):771-780.
doi: 10.1001/jamacardio.2021.0669.

Cardiovascular Biomarkers in the Early Discrimination of Type 2 Myocardial Infarction

Thomas Nestelberger  1   2   3 , Jasper Boeddinghaus  1   2 , Pedro Lopez-Ayala  1   2 , Thomas E Kaier  4 , Michael Marber  4 , Vincent Gysin  1   2 , Luca Koechlin  1   2   5 , Ana Yufera Sanchez  1   2 , Maria Rubini Giménez  1   2   6 , Desiree Wussler  1   2 , Joan Elias Walter  1   2 , Ivo Strebel  1   2 , Tobias Zimmermann  1   2 , Noemi Glarner  1   2 , Òscar Miró  2   7 , F Javier Martin-Sanchez  2   8 , Tatjana Zehnder  1   2 , Raphael Twerenbold  1   2 , Dagmar I Keller  9 , Christian Mueller  1   2 ; APACE Investigators
Collaborators, Affiliations
Multicenter Study

Cardiovascular Biomarkers in the Early Discrimination of Type 2 Myocardial Infarction

Thomas Nestelberger et al. JAMA Cardiol. .

Abstract

Importance: Rapid and accurate noninvasive discrimination of type 2 myocardial infarction (T2MI), which is because of a supply-demand mismatch, from type 1 myocardial infarction (T1MI), which arises via plaque rupture, is essential, because treatment differs substantially. Unfortunately, this is a major unmet clinical need, because even high-sensitivity cardiac troponin (hs-cTn) measurement provides only modest accuracy.

Objective: To test the hypothesis that novel cardiovascular biomarkers quantifying different pathophysiological pathways involved in T2MI and/or T1MI may aid physicians in the rapid discrimination of T2MI vs T1MI.

Design, setting, and participants: This international, multicenter prospective diagnostic study was conducted in 12 emergency departments in 5 countries (Switzerland, Spain, Italy, Poland, and the Czech Republic) with patients presenting with acute chest discomfort to the emergency departments. The study quantified the discrimination of hs-cTn T, hs-cTn I, and 17 novel cardiovascular biomarkers measured in subsets of consecutively enrolled patients against a reference standard (final diagnosis), centrally adjudicated by 2 independent cardiologists according to the fourth universal definition of MI, using all information, including cardiac imaging and serial measurements of hs-cTnT or hs-cTnI.

Results: Among 5887 patients, 1106 (18.8%) had an adjudicated final diagnosis of MI; of these, 860 patients (77.8%) had T1MI, and 246 patients (22.2%) had T2MI. Patients with T2MI vs those with T1MI had lower concentrations of biomarkers quantifying cardiomyocyte injury hs-cTnT (median [interquartile range (IQR)], 30 (17-55) ng/L vs 58 (28-150) ng/L), hs-cTnI (median [IQR], 23 [10-83] ng/L vs 115 [28-576] ng/L; P < .001), and cardiac myosin-binding protein C (at presentation: median [IQR], 76 [38-189] ng/L vs 257 [75-876] ng/L; P < .001) but higher concentrations of biomarkers quantifying endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress (median [IQR] values: C-terminal proendothelin 1, 97 [75-134] pmol/L vs 68 [55-91] pmol/L; midregional proadrenomedullin, 0.97 [0.67-1.51] pmol/L vs 0.72 [0.53-0.99] pmol/L; midregional pro-A-type natriuretic peptide, 378 [207-491] pmol/L vs 152 [90-247] pmol/L; and growth differentiation factor 15, 2.26 [1.44-4.35] vs 1.56 [1.02-2.19] ng/L; all P < .001). Discrimination for these biomarkers, as quantified by the area under the receiver operating characteristics curve, was modest (hs-cTnT, 0.67 [95% CI, 0.64-0.71]; hs-cTn I, 0.71 [95% CI, 0.67-0.74]; cardiac myosin-binding protein C, 0.67 [95% CI, 0.61-0.73]; C-terminal proendothelin 1, 0.73 [95% CI, 0.63-0.83]; midregional proadrenomedullin, 0.66 [95% CI, 0.60-0.73]; midregional pro-A-type natriuretic peptide, 0.77 [95% CI, 0.68-0.87]; and growth differentiation factor 15, 0.68 [95% CI, 0.58-0.79]).

Conclusions and relevance: In this study, biomarkers quantifying myocardial injury, endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress provided modest discrimination in early, noninvasive diagnosis of T2MI.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Nestelberger has received research support from the Swiss National Science Foundation (grant P400PM_191037/1), the Professor Dr Max Cloëtta Foundation, the Margarete und Walter Lichtenstein-Stiftung (grant 3MS1038), University Basel, and the University Hospital Basel, as well as speaker/consulting honoraria from Siemens, Beckman Coulter, Bayer, Ortho Clinical Diagnostics, and Orion Pharma outside the submitted work. Dr Boeddinghaus has received research grants from the University of Basel and the Division of Internal Medicine, the Swiss Academy of Medical Sciences, and the Gottfried and Julia Bangerter-Rhyner-Foundation and speaker honoraria from Siemens outside the submitted work. Dr Boeddinghaus also reported personal fees from Siemens, Roche, Ortho Clinical Diagnostics, and Quidel Corporation outside the submitted work. Dr Twerenbold has received research support from the Swiss National Science Foundation (grant P300PB-167803/1), the Swiss Heart Foundation, the Swiss Society of Cardiology, the Cardiovascular Research Foundation Basel, the University of Basel, and the University Hospital Basel and speaker/consulting honoraria from Roche, Abbott, Amgen, AstraZeneca, Brahms, Singulex, Siemens, and Thermo Scientific outside the submitted work. Dr Badertscher has received research funding from the Stiftung für Herzschrittmacher und Elektrophysiologie outside the submitted work. Dr Wildi has received research funding from the FAG Basel and the Julia und Gottfried Bangerter-Rhyner Stiftung. Dr Rubini Giménez has received speaker honoraria from Abbott and research support from the Swiss Heart Foundation outside the submitted work. Dr Walter reported receiving research grants from the Swiss Academy of Medical Sciences, the Bangerter Foundation (grant YTCR 23/17), and the Swiss Heart Foundation outside the submitted work. Dr Martin-Sanchez has received speaker, advisory, or consulting fees from Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Pfizer, the Medicines Company, Otsuka, ThermoFisher, Cardiorentis, and Sanofi and research grants from the Spanish Ministry of Health and FEDER, Mapfre, Novartis, Bayer, Merck Sharp & Dohme, Abbott, and Orion-Pharma outside the submitted work. Dr Kaier was supported by a clinical research fellowship grant by the British Heart Foundation (grant FS/15/13/31320) and a National Institute on Health Research clinical lectureship (grant CL-2019-17-006). Prof Marber was supported by grants from the Medical Research Council (grant G1000737), Guy's and St Thomas' Charity (grants R060701 and R100404), British Heart Foundation (grant TG/15/1/31518), and the UK Department of Health through the National Institute for Health Research Biomedical Research Centre award to Guy's & St Thomas' National Health Service Foundation Trust and is named as an inventor on a patent held by King’s College London for the detection of cardiac myosin-binding protein C as a biomarker of myocardial injury. Dr Reichlin has received research grants from the Goldschmidt-Jacobson Foundation, the Swiss National Science Foundation, the Swiss Heart Foundation, the European Union, the Professor Max Cloëtta Foundation, the Cardiovascular Research Foundation Basel, the University of Basel, the University Hospital Basel, and Biosense-Webster and has received speaker/consulting honoraria or travel support from Abbott, AstraZeneca, Brahms, Bayer, Biosense-Webster, Medtronic, Pfizer/Bristol Myers Squibb, St. Jude Medical, and Roche outside the submitted work. Dr Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the Stiftung für Kardiovaskuläre Forschung Basel, Abbott, Alere, AstraZeneca, Beckman Coulter, Biomerieux, Brahms, Roche, Siemens, Singulex, Sphingotec, and the Department of Internal Medicine, University Hospital Basel, as well as speaker/consulting honoraria from Abbott, Alere, AstraZeneca, Biomerieux, Boehringer-Ingelheim, Bristol Myers Squibb, Brahms, Cardiorentis, Novartis, Roche, Siemens, and Singulex outside the submitted work. Dr Mueller reported grants, personal fees, and nonfinancial support from 8sens.biognostic GmbH, Abbott Laboratories, Roche Diagnostics, Nunc, Athera Biotechnologies, Millipore Sigma, and Brahms AG for the measurement of biomarkers and/or reagents during the conduct of the study and outside the submitted work. Dr Koechlin reported grants from University of Basel, Schweizerische Akademie der Medizinischen Wissenschaften, and Freiwillige Akademische Gesellschaft Basel outside of the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Boxplots for High-Sensitivity Cardiac Troponin T and I Concentrations
Concentrations of high-sensitivity cardiac troponin T (measured in 851 patients with type 1 myocardial infarction [MI] and 246 patients with type 2 MI) and high-sensitivity cardiac troponin I (848 patients with type 1 MI and 241 patients with type 2 MI) at presentation, and 1 hour and 2 hours after presentation in patients with type 1 MI vs type 2 MI. Boxes represent medians and the interquartile ranges. aStatistically significant differences between groups (P < .01).
Figure 2.
Figure 2.. Boxplots of 4 Biomarkers in Patients With Type 1 and Type 2 Myocardial Infarction (MI)
Concentrations of cardiac myosin-binding protein C (measured in 303 patients with type 1 MI and 105 patients with type 2 MI) at baseline (0 hours), midregional pro–A-type natriuretic peptide (measured in 97 patients with type 1 MI and 37 patients with type 2 MI), C-terminal proendothelin 1 measured in 97 patients with type 1 MI and 37 patients with type 2 MI), and growth differentiation factor 15 (measured in 91 patients with type 1 MI and 37 patients with type 2 MI) in patients with type 1 MI vs type 2 MI. Boxes represent medians and the interquartile ranges. The eFigure in Supplement 1 presents data on all biomarkers. aStatistically significant differences between groups (P < .05).
See this image and copyright information in PMC

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