APACE researchers conclude that clinical parameters are still most reliable

Although biomarkers can quantify endothelial and microvascular dysfunction and hemodynamic stress in the early diagnosis of type 2 myocardial infarction (T2MI) to distinguish it from type 1 MI (T1MI), clinical parameters are still the most reliable way to identify patients with T2MI, according to results from the APACE trial, published in JAMA Cardiology.

“Because treatments differ substantially, the early and accurate discrimination of T2MI is a major yet largely unmet clinical need. Unfortunately, established biomarkers of cardiomyocyte injury, including high-sensitivity cardiac troponin (hs-cTn) T and I levels, have only modest diagnostic discrimination,” wrote researchers led by Thomas Nestelberger, MD, of the University of Basel, Basel, Switzerland.

In an accompanying editorial, Marc S. Sabatine, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and Deputy Editor of JAMA Cardiology, agreed.

“Differentiating between type 1 and type 2 MI is clinically important because the therapeutic focus differs. For patients with type 1 MI, the focus is on aggressive antithrombotic therapy and consideration of urgent coronary angiography and revascularization. For patients with type 2 MI, the focus is on treating the extracardiac stressor precipitating the myocardial oxygen supply and demand imbalance,” he wrote.

For the international, multicenter, prospective APACE study—conducted in 12 emergency departments in five countries including Switzerland, Spain, Italy, Poland, and the Czech Republic—Nestelberger and colleagues included 5,887 patients (median age: 61 years; 32.6% women) who presented with acute chest discomfort. Researchers quantified the ability of high-sensitive cardiac troponin T (hs-cTn T), high-sensitivity cardiac troponin I (hs-cTn I), and 17 new cardiovascular biomarkers against a reference standard to distinguish T2MI from T1MI.

They defined T1MI as spontaneous MI that was associated with a primary atherothrombotic coronary event (such as plaque erosion/rupture, intraluminal coronary thrombus, or distal microembolization) in addition to clinically evident myocardial necrosis indicative of acute MI, and T2MI as MI that occurred secondary to a mismatch of oxygen supply-demand, as evidenced by bradyarrhythmias or tachyarrhythmias, hypoxemia, hypotension, hypertension, severe anemia, coronary artery spasm, coronary dissection, or coronary embolism.

Nestelberger and fellow researchers further specified: “As recommended, the documentation of a clear trigger was essential for the diagnosis of T2MI. Also, coronary angiography was not mandatory for a diagnosis of T1MI, which limited the possible effect of selection bias because of clinical referral to coronary angiography.”

In all, 18.8% of patients received a final diagnosis of MI, among whom 77.8% had T1MI and 22.2% had T2MI. Patients with T2MI versus T1MI were more often women (36.2% vs 26.2%, respectively; P=002), were more often tachycardic (24.4% vs 2.6%; P˂0.001) and hypotensive (2.8% vs 0.8%; P=0.02), and had previous MI less frequently (26.8% vs 34.3%; P=0.03).

Lower concentrations of the biomarkers that quantify cardiomyocyte injury hs-cTn T were seen in patients with T2MI compared with those with T1MI (median: 30 vs 58 ng/L, respectively), as were lower concentrations of hs-cTn I (median: 23 vs 115 ng/L; P˂0.001) and cardiac myosin-binding protein C (cMyC; median at presentation: 76 vs 257 ng/mL; P˂0.001).

However, patients with T2MI also had higher concentrations of biomarkers that quantified endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress, as follows:

  • C-terminal proendothelin (CT-proET-1): 1: 97 vs 68 pmol/L.
  • Midregional proadrenomedullin: 0.97 vs 0.72 pmol/L.
  • Midregional pro-A-type natriuretic peptide: 378 vs 152 pmol/L.
  • Growth differentiation factor 15 (GDF15): 2.26 vs 1.56 ng/L (all P˂0.001).

Nestelberger et al noted, however, that the discrimination for these biomarkers was modest, as measured by the area under the receiver operating characteristics curve:

  • hs-cTn T: 0.67.
  • hs-cTn I: 0.71.
  • cardiac myosin-binding protein C: 0.67.
  • cMyC: 1: 0.73.
  • midregional proadrenomedullin: 0.66.
  • midregional pro-A-type natriuretic peptide (MRproANP): 0.77.
  • GDF15: 0.68.

According to Sabainte, previous research found that patients with T1MI have higher levels of high-sensitivity cardiac troponin (hsTn) compared with those with T2MI, but the ranges show considerable overlap. Other studies have tested other biomarkers, showing that some of the biomarkers of hemodynamic stress are higher in T2MI compared with T1MI, including MRproANP.

“Nestelberger et al have added to this literature by examining a broad array of cardiovascular biomarkers in a larger cohort. They, too, found that MRproANP and C-terminal proendothelin-1 levels were higher in those with type 2 MI than in those with type 1 MI. But ultimately, no biomarkers were convincingly superior to hsTn at 2 hours after presentation,” he wrote.

“Thus, for now, 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,” concluded Sabatine.

  1. Biomarkers quantifying endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress provided modest discrimination in the early, noninvasive diagnosis of T2MI vs T1MI.

  2. Clinical parameters may remain the only reliable means for the identification of patients with T2MI.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Nestelberger has received research support from the Swiss National Science Foundation, the Professor Dr Max Cloëtta Foundation, the Margarete und Walter Lichtenstein-Stiftung, 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.

Sabatine reported grants from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia Therapeutics, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; 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; and is a member of the TIMI Study Group, which has also received institutional research grant support from Brigham and Women’s Hospital from Abbott Laboratories, Regeneron, Roche, and Zora Biosciences.

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Topic ID: 74,358,730,358,192,925