European Heart Journal (2005) 26, 2349–2350
doi:10.1093/eurheartj/ehi599
Mirror, mirror on the wall: the quest for the earliest
marker of myocardial ischaemia
Evangelos Giannitsis, and Hugo A. Katus*
Department of Cardiology, Medizinische Universitaätsklinik Heidelberg, Abteilung für Innere Medizin III, Im Neuenheimer
Feld 410, 69120 Heidelberg, Germany
Online publish-ahead-of-print 11 October 2005
This editorial refers to ‘Serum deoxyribonuclease I
activity can be used as a sensitive marker for detection
of transient myocardial ischaemia induced by percuta-
neous coronary intervention’† by K. Arakawa et al., on
page 2375
In patients with acute ST-segment elevation myocardial
infarction (STEMI), the diagnosis and immediate initiation
of reperfusion therapy is based on the standard 12-lead
ECG. Owing to the fact that cardiac markers appear in the
blood a substantial time after the onset of symptoms,
cardiac markers are neither helpful for early diagnosis of
patients with STEMI nor should results be awaited before
initiation of recanalization therapy.
Unfortunately, at least 40% of all patients with confirmed
acute myocardial infarction (AMI) show no diagnostic ECG
changes on admission.1 In these patients with suspected
acute coronary syndrome (ACS), cardiac troponins have
become the biochemical gold standard for classification,
risk stratification, and guidance of therapy.1 Cardiac
troponins owe their exclusive superiority to their cardiospe-
cificity, which indicates myocardial necrosis, and to their
higher sensitivity compared with creatine kinase. However,
obviously myocardial necrosis is a prerequisite for appear-
ance of troponins in the blood, and the inflicting event
needs to have occurred a few hours earlier.2
Novel cardiac markers ideally should improve these limit-
ations by appearing earlier in the blood in case of an AMI,
or by allowing identification of myocardial ischaemia in
advance, or even in the absence of myocardial infarction.
Needless to say that markers suitable in clinical routine
should not be increased in healthy individuals or during
ischaemia, inflammation, or injury of non-cardiac tissue.
Hitherto, free fatty acids unbound to albumin and ischae-
mia-modified albumin (IMA) have been proposed as biochemi-
cal markers of cardiac ischaemia. Of these markers, most
information is available for IMA. After initial enthusiasm,
recent and more thorough work indicates that IMA is specific
The opinions expressed in this article are not necessarily those of the
Editors of the European Heart Journal or of the European Society of
Cardiology.
* Corresponding author. Tel: þ49 6221 56 8670.
E-mail address: hugo_katus@med.uni-heidelberg.de
{
doi:10.1093/eurheartj/ehi288
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Editorial
neither for myocardial ischaemia nor for infarction. Thus,
reduced cobalt binding has also been reported after
endurance exercise, such as marathon race, after radiofre-
Downloaded from eurheartj.oxfordjournals.org by guest on September 28, 2010
quency catheter ablation, after skeletal muscle ischaemia,
or in patients with peripheral vascular disease, as well as in
diseases associated with oxidative stress such as systemic
sclerosis.3,4 Impaired cobalt binding has been related to
structural changes of the NH2 terminus of albumin occurring
during hypoxia, acidosis, or free radical damage. Findings in
patients with systemic sclerosis and experimental data
indicate that serum albumin may be modified more likely by
reperfusion after an ischaemic event than by ischaemia
itself.4
In essence, IMA does not appear to fulfil the criteria of an
ideal marker of myocardial ischaemia and its results must be
interpreted cautiously, taking into consideration clinical
circumstances and comorbidity.
Arakawa et al. 5 introduce serum DNase I activity,
measured with a novel rapid assay, as a new marker for
early and sensitive detection of myocardial ischaemia. In
the present report, the authors were able to show that
serum DNase I activity rose 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. On the basis of these findings, the
authors claimed that serum DNase I activity might serve
as an earlier and more sensitive biochemical marker of
reversible myocardial ischaemia.
In a recent publication, the same authors reported an
increased DNase I activity in AMI patients.6 DNase I activity
was elevated within 3 h after the onset of pain, suggesting
that DNase I might also be useful for earlier diagnosis of
AMI. This time gap of 3 h from onset of symptoms to
elevation in the blood is not different for myoglobin or tro-
ponins measured by sensitive assays and lower diagnostic
cut-off values. Furthermore, in that earlier study the same
authors found that DNase I activity in patients with stable
or unstable angina or in patients with stroke, trauma,
renal failure, or chronic heart failure was not different
from serum DNase I activity in healthy controls.6
How can serum DNase be a sensitive and early marker of
myocardial ischaemia in patients undergoing elective PCI but
not in symptomatic patients with stable or unstable angina?
2350
The exact pathomechanism responsible for DNase I
elevation is still unknown. DNase I is not a cardiospecific
enzyme, as it is present in biological fluids and is ubiqui-
tously expressed in mammalian tissues. DNase I is an endo-
nuclease that preferentially degrades double-stranded DNA
in a Ca2þ-dependent manner to produce oligonucleotides
with 50 -phospho and 30 -hydroxy termini.
There is also a consistent body of evidence suggesting that
DNase I is involved in DNA breakdown during apoptosis in
patients with cardiomyopathy.7
In the present publication, balloon angioplasty and pro-
visional coronary stenting were used as a model to induce
reversible myocardial ischaemia. However, PCI has several
shortcomings and is not an ideal model to evaluate the
effects of myocardial ischaemia. First, a substantial pro-
portion of patients undergoing elective coronary interven-
tions develop peri-interventional myocardial infarction
because of side branch occlusion, major coronary dissec-
tion, dislodgement of visible thrombus, or distal emboliza-
tion of platelet microaggregates. Secondly, brisk
repetitive inflations of the balloon at high pressures and
coronary stenting will cause endothelial injury or plaque
disruption, resulting in release of plaque debris that
might represent a target for reactive oxygen species.8
Thirdly, short episodes of myocardial ischaemia during
PCI have been shown to induce reperfusion injury as
suggested by sustained oxidative stress detectable in the
venous effluent of reperfused myocardium.9 Priming of
neutrophils and induction of oxidative stress after elective
PCI, however, are not necessarily associated with myocar-
dial ischaemia.10
In summary, the potential applicability of DNase I activity
for non-invasive detection of myocardial ischaemia remains
to be defined. Up to now, there is very little and inconsistent
evidence that increased endonuclease activity is specific
either for myocardial infarction or even for myocardial
ischaemia. Conversely, it is tempting to speculate that the
same mechanisms involved in the structural modification
of albumin during balloon angioplasty may also affect
activity of DNase I in the blood. Thus, whether DNase
activity results exclusively from myocardial ischaemia
marker or is rather the result of a complex mechanism
involving acidosis, reperfusion injury, or oxidative stress
remains to be determined.
Further studies are required to characterize precisely the
characteristics of this marker and to test the predictive
power in unselected clinical cohorts of chest pain patients
Editorial
before DNase I activity can become a diagnostic tool for
patients with suspected ACS.
Conflict of interest: H.A.K. has developed the cardiac
troponin T assay and holds a patent jointly with Roche
Diagnostics. E.G. and H.A.K. have received honoraria for
lectures from MSD, Roche Diagnostics, Novartis,
AstraZeneca, Sanofi and Bayer.
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