Hope, but No Home Runs: Biomarker Distinction Between MI Types

Troponins, widely used to help confirm or rule out acute myocardial infarction (MI), aren’t as helpful in separating different MI types. They aren’t very reliable for discriminating between, for example, the atherothrombotic type (T1) MI and the oxygen supply–demand mismatch type (T2) MI.

But other biomarkers that better reflect distinct pathophysiologies could potentially tease out their identities more accurately.

A prospective cohort study provides suggestive evidence for at least four such biomarkers, which “showed modest promise for the early discrimination of T2 MI” among patients with suspected acute coronary syndromes at emergency departments in five European countries.

Circulating levels of the two dozen tested molecules were thought to reflect not only myocardial injury but hemodynamic stress, endothelial dysfunction, inflammation, and other processes not precisely captured by commonly used high-sensitivity assays for cardiac troponins I and T (hs-cTnI and hs-cTnT, respectively).

Most of the evaluated biomarkers were found at similar levels in the patients with either confirmed T1 or T2 MI, “and were therefore not helpful in their discrimination,” investigators note in their April 21 publication in JAMA Cardiology. But a few emerged as possible contenders in multivariate analysis.

In particular, levels of mid-regional pro-A-type natriuretic peptide (MR-proANP), thought to reflect hemodynamic stress, seemed to add useful information to clinical features in identifying patients with T2 MI, report the authors, led by Thomas Nestelberger, MD, University of Basel, Switzerland.

Expeditious therapy is important for both T1 and T2 MI but is also likely to differ between types, so separating the two diagnoses early can be critical. Type 2 MI, according to the consensus-based 4th Universal Definition of Myocardial Infarction (UDMI-4), is caused by an ischemic surge in myocardial oxygen demand or drop in its supply secondary to a wide array of cardiac and noncardiac primary causes, whereas T1 MI is characterized by spontaneous coronary plaque rupture with thrombosis and consequent myocardial ischemia.

But in the current study, none of the assessed biomarkers provided a diagnostic edge over troponins when considered with clinical information. “We tried to combine several biomarkers to improve the diagnostic accuracy, to distinguish between T1 MI and T2 MI. However, there was no additional benefit,” Nestelberger told theheart.org | Medscape Cardiology.

“Further studies are definitely necessary regarding the usefulness of additional biomarkers such as d-dimer,” he said, which is a marker of hemostatic activation that was not included in the current analysis.

“In the meantime, invasive coronary angiography remains the mainstay to differentiate accurately between T1 MI and T2 MI in most patients.”

The three other molecules that showed some discriminating power, other than troponins or old-school creatine kinase-myocardial band (CK-MB), were:

  • C-terminal proendothelin 1 (CT-proET-1), thought to be a marker of endothelial dysfunction

  • mid-regional proadrenomedullin (MR-proADM), believed related to microvascular and endothelial function

  • growth differentiation factor 15 (GDF 15), seen as a marker for hemodynamic stress, inflammation, and vascular aging, the authors observe.

The biomarker assays were conducted as part of the prospective Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) cohort study, which provided the current analysis with 5887 eligible participants who presented from 2006 to 2018 to hospitals in the Czech Republic, Italy, Poland, Spain, and Switzerland.

All patients, about one-third of whom were women, showed either a rise or fall in troponin levels consistent with UDMI-4 criteria for T1 MI. Ultimately, after adjudication conducted for the current analysis, 18.8% of patients were assigned a diagnosis of MI. Of those 1106 patients, 77.8% were diagnosed with T1 MI and the remaining 22.2% received a final diagnosis of T2 MI.

Mean levels of hs-cTnI and hs-cTnT at presentation were consistently lower in T2 MI than in T1 MI, but the wide confidence intervals prevented either myocardial stress biomarker from usefully separating the two diagnoses.

Concentrations of cardiac myosin-binding protein C (cMyC), “which may quantify cardiomyocyte injury even more accurately than hs-cTnT or hs-cTnI levels, were lower in T2 MI vs T1 MI and provided modest diagnostic accuracy comparable” to that of the troponins, the report notes.

Indeed, of all the biomarkers tested, those related to cardiac myocyte injury tended to be at lower concentrations in T2 MI than in T1 MI. But “biomarkers quantifying endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress” tended to be at higher levels in T2 MI, the group writes.

The new analysis adds to the extensive literature in the field by covering “a broad array of cardiovascular biomarkers in a larger cohort,” observes an accompanying editorial from JAMA Cardiology deputy editor Marc S. Sabatine, MD, MPH, Brigham and Women’s Hospital, Boston.

The new findings replicate previous research in finding higher levels of MR-proANP and CT-proET-1 in patients diagnosed with T2 MI, he writes. “But ultimately, no biomarkers were convincingly superior to hs-Tn at 2 hours after presentation.”

So, for now, says Sabatine, “the differentiation between type 1 and type 2 MI still requires the clinician to integrate all of the available data for each patient and make an informed, albeit imperfect, judgment.”

The study was supported by grants from Abbott, Beckman Coulter, Biomerieux, Brahms, Roche, Siemens, and Singulex. “All investigated assays were donated by the manufacturers: 8sens.biognostic, Abbott Laboratories, Roche Diagnostics, Nunc, Athera Biotechnologies, Millipore Sigma, and Brahms.” Nestelberger discloses receiving honoraria for speaking or consulting from Siemens, Beckman Coulter, Bayer, Ortho Clinical Diagnostics, and Orion Pharma; disclosures for the other authors are in the report. Sabatine discloses receiving grants from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia Therapeutics, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and personal fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dr Reddy’s Laboratories, Dyrnamix, IFM Therapeutics, Intarcia Therapeutics, The Medicines Company, MedImmune, and Merck. Sabatine is a member of the TIMI Study Group, which has received institutional research support from Abbott Laboratories, Regeneron, Roche, and Zora Biosciences.

JAMA Cardiol. Published online April 21, 2021. Abstract, Editorial

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