Ability of DNase I activity to detect myocardial ischaemia in vasospastic angina a view through a monocle?

The detection of myocardial ischaemia earlier or in the absence of myocardial infarction is challenging and has the potential to improve the process of triage of patients with acute coronary syndrome (ACS). Still, cardiac troponins represent the gold standard for the biochemical diagnosis of acute myocardial infarction, for the classification and risk stratification of ACS, and for the objective guidance of anti-ischaemic therapies.1 New biomarkers are frequently pushed forward with the claim to be more specific, more sensitive, or to appear earlier in blood than cardiac troponins. Until now, all of these cardiac biomarkers failed to gain general acceptance due to specific limitations. Myoglobin and to a lesser extent creatine kinase (CK)-MB are released from heart and skeletal muscle and thus lack absolute cardiospecificity. Both myoglobin and CK-MB mass have been claimed to appear earlier in blood. However, recent data suggest that cardiac troponins may become detectable earlier in blood than myoglobin or CK-MB mass just by lowering the decision cut-off point to the 10% coefficient of variation (CV) or 99th percentile value.2 After initial enthusiasm, the role of novel cardiac biomarkers such as ischaemia-modified albumin (IMA) or heart-type fatty acid-binding protein (h-FABP) as earlier markers of myocardial ischaemia is still unsettled.3,4 In 2005, Arakawa and co-workers introduced DNase I activity, measured with a novel rapid assay, as a new marker for early and sensitive detection of myocardial ischaemia.5 The authors were able to demonstrate that serum DNase I activity increased significantly after elective percutaneous coronary intervention (PCI) of single vessel disease in patients with stable angina. DNase I activity increased much earlier than cardiac troponin-T or CK-MB, and the number of patients with abnormal DNase activity exceeded the number of subjects with detectable cardiac troponin-T levels. The accompanying editorial from Giannitsis and Katus that referred to that publication5 outlined that studies that use PCI as a model to induce myocardial ischaemia have to be interpreted cautiously.6 PCI has several shortcomings and is not an ideal model to evaluate the effects of myocardial ischaemia. In order to overcome these shortcomings, Morikawa and co-workers7 used a different model, namely vasospastic angina that is seemingly free of the obstacles of PCI, to prove that DNase I activity is a sensitive marker of myocardial ischaemia. First of all, the authors have to be congratulated for their insistence and continuous scientific work in the field of new biomarkers. The authors enrolled 29 patients with suspected vasospastic angina pectoris (VSAP) and controls who underwent diagnostic catheterization for suspected coronary heart disease. In order to provoke coronary spasm, ergonovine maleate was injected into either the left or the right coronary artery of the 29 patients through a catheter. The diagnosis of VSAP was made in the presence of ST-segment shifts, occurrence of angina pectoris, and TIMI grade flow 0 or 1 in the coronary angiogram. DNase I activity was measured repeatedly, and an intra-individual percentage difference of >12.4% was considered positive. All patients with a positive provocation test demonstrated a significant elevation of serum DNase I activity 3 h after the test, and the activity level tended to return to baseline by 24 h. In contrast, cardiac troponin T and CK-MB did not increase above the 99th percentile concentration cut-off point, leading the authors to the conclusion that DNase I activity is a more specific and earlier marker for myocardial ischaemia. However, the VSAP model is not adequate to prove beyond doubt that the increase in DNase I activity is due to myocardial ischaemia for several reasons. First, DNase I is an endonuclease that preferentially attacks double-stranded DNA in a Ca2+-dependent manner to produce oligonucleotides with 5′-phospho and 3′-hydroxy termini. Thus, DNase I is not a cardiospecific enzyme, as it is present in biological fluids and is ubiquitously expressed in mammalian tissues. Accordingly, previous studies have demonstrated that DNase I activity is associated with apoptosis in dilated or ischaemic cardiomyopathy,8,9 after elective PCI,5 and after acute myocardial infarction.10 Secondly, coronary vasospasm may cause myocardial ischaemia, although longer periods may be needed to induce detectable myocardial ischaemia or even myocardial infarction. However, if the authors claim that a 12.4% increase of DNase I activity is due to myocardial ischaemia, which is the reference standard that objectively confirms the presence of myocardial ischaemia? Several confounding variables have to be considered such as haemodynamic alterations including an increase of blood pressure and heart rate (both were actually seen only in the VSAP-positive cases), a rise of left ventricular end-diastolic pressure or pulmonary artery pressure, and potential effects of numerous compounds released into the circulation from endothelium and activated blood cells.11 These compounds include vasoactive hormones such as endothelin, histamine, and natriuretic peptides, secretory products of platelets such as serotonin, thromboxane, platelet-activating factor, and soluble CD 40 ligand, formation of reactive oxygen species, and activation of leukocytes, adhesion molecules, and inflammatory proteins including interleukins, tumour necrosis factor, and metalloproteinases, all of them potentially involved in the process of apoptosis.12–16 Unfortunately, the present study does not provide any information on these interesting aspects on the pathophysiology of coronary vasospasm. In conclusion, vasospastic angina is not a simple model for the evaluation of myocardial ischaemia but is in fact rather complex, raising more questions than answers. At the moment, the finding that DNase I activity increases in vasospastic angina is interesting, but myocardial ischaemia is only one of numerous potential reasons for its increase. Conflict of interest: none declared.