University Hospital, Cardiology,
Bern, Switzerland
To the Editor:
Although the article by Leesar and coworkers in the June 3, 1997,
issue of Circulation1 concludes that
"adenosine preconditions human myocardium," in
our opinion their investigation in 30 patients undergoing balloon
angioplasty (PTCA) and pretreatment with normal saline or
adenosine (2 mg/min for 10 minutes) merely allows them to
reiterate their introductory statement that "to the best of our
knowledge, evidence that adenosine can precondition human
myocardium in vivo is still lacking." First of all, the
fact that there have been recent studies demonstrating reduced signs of
myocardial ischemia during repeated balloon inflations does not
necessarily suggest the existence of ischemic preconditioning
in the conventional, ie, biochemical, sense. As long as the
contribution of the gradual opening of collateral channels with
successive balloon occlusions is not accounted for in the observed
phenomenon of attenuated myocardial ischemia, ischemic
"preconditioning" may be not a biochemical but a biophysical
process of collateral recruitment due to the temporally increasing
effect of a pressure gradient across the anastomoses between the
nonstenotic donor vessel and the occluded recipient vessel.
Hence, the finding that such a thing as ischemic
preconditioning, in the normally used sense of the word, exists in
humans is very controversial and is inversely associated with whether
or not the authors accounted for collaterals.2
Second, and considering the effects of adenosine on the
resistance and conductance vessels of the coronary circulation,
it is similarly disputable whether there is such a thing as
adenosine-induced preconditioning or whether the phenomenon of
mitigated myocardial ischemia during coronary occlusion
on adenosine administration is actually
pharmacologically induced collateral recruitment. After all,
exogenously administered adenosine is known to cause not only
profound microvascular coronary
dilatation3 but also increased flow indexes
through collateral channels.4 Therefore, as long
as Leesar et al do not treat coronary collaterals as a
covariable in the outcome of reduced myocardial ischemia in
response to adenosine administration before PTCA, they cannot
conclude that "adenosine preconditions human
myocardium," or else the scientific community has to
redefine preconditioning by extending its meaning to
hemodynamic events such as enhanced flow along an
increased (collateral) pressure gradient.
Finally, it is hard to imagine that the ST-segment shifts of the
intracoronary ECGs shown in Figure 1 of the article by Leesar
et al amount to 20 mm and more (up to 60 mm). The
y axis of this graph must have been mixed up with that of
Figure 2 illustrating the summed ST-segment shifts of all 11 surface
ECG leads.
References
Division of Cardiology,
University of Louisville Health Sciences Center,
Louisville, Ky
Contrary to what Seiler et al assert, several studies
support the notion that alleviation of ischemia after the first
balloon inflation during PTCA is a manifestation of ischemic
preconditioning (PC). Although Seiler et al cite a paper by Dupouy et
al1 as evidence that ischemic PC does not
exist in humans, the results of that study do not support the
conclusions of the authors for reasons that have been detailed
elsewhere.2 Seiler and colleagues assert "the
finding that such a thing as ischemic preconditioning ...
exists in humans is ... inversely associated with whether or not
the authors accounted for collaterals." This assertion is
incorrect. Although Cribier et al3 found
increased collateral perfusion during subsequent balloon inflations,
they observed that in individual cases, myocardial ischemia
decreased with repeated inflations despite the fact that there was no
evidence of improved collateral circulation. Thus, the increased
tolerance to ischemia did not correlate with indexes of
collateral function.3 In patients undergoing PTCA
of the left anterior descending coronary artery, Tomai et
al4 demonstrated that the average peak flow
velocity recorded in the right coronary artery during the
first and second balloon inflation (an index of collateral recruitment)
was not significantly different, yet there was increased tolerance to
ischemia during the second inflation. In that
study,4 only
A recent study by Sakata et al6
demonstrates that enhanced tolerance to ischemia occurred in
patients undergoing PTCA in whom there was no recruitable collateral
circulation during balloon inflation, as assessed by myocardial
contrast echocardiography. Unlike coronary
angiography, which only detects collateral vessels with a diameter
>100 µm, contrast echocardiography reflects
myocardial perfusion in the occluded bed and therefore is a more
sensitive technique. These studies4 6 indicate
that ischemic PC develops during repetitive balloon inflations
in the course of PTCA independently of changes in collateral
perfusion.
It should also be pointed out that evidence of collateral recruitment
during PTCA has been found in only
Seiler et al speculate that in our study,7
administration of adenosine caused enhanced tolerance to
ischemia during the first inflation simply by inducing
collateral recruitment. This speculation is unsupportable for several
reasons. First, we allowed a 10-minute interval between the end of the
adenosine infusion and the first balloon inflation. The plasma
half-life of adenosine in humans is on the order of seconds. We
have recently studied 3 patients in whom we infused
intracoronary adenosine at the same dose used in our
previous study7 (2 mg/min for 10 minutes) and
measured coronary flow with a 0.014-in Doppler guidewire
and quantitative coronary angiography at baseline, at the end
of adenosine infusion, and 5 and 10 minutes later. In all 3
patients, adenosine-induced hyperemia subsided
completely within 10 minutes of the end of the adenosine
infusion. Therefore, any vasodilation induced by adenosine in
our study7 should have resolved before the first
balloon inflation. Second, Seiler et al seem to confuse the effects of
intravenous adenosine with those of
intracoronary adenosine. In order for collateral flow
to increase in the presence of a complete coronary occlusion,
collateral vessels need to be dilated in their entire length, not just
within the collateral-dependent vascular bed. Because in our study
adenosine was administered by the intracoronary route
and produced no changes in systemic hemodynamics, it
seems unlikely that adenosine dilated the portion of collateral
vessels that was outside of the collateral-dependent vascular bed. (In
contrast, intravenous adenosine may dilate the
entire length of collateral vessels.) Taken together, the above
considerations strongly support the conclusion that the enhanced
tolerance to ischemia after pretreatment with
adenosine7 was unrelated to increased
collateral perfusion.
With regard to the measurements of ST-segment shifts on the
intracoronary ECG, it would appear that Seiler and coworkers
are not familiar with the pertinent literature. Numerous previous
studies have reported ST-segment shifts >1 mV (10 mm) during
PTCA4 8 9 10 (reviewed in Reference 2). In these
studies, ST-segment elevation has been found to be much lower in the
surface ECG than in the intracoronary ECG. Obviously, the
precise magnitude of the ST-segment shifts can vary depending on a
number of factors, including, among others, the size of the
ischemic region, the exact position of the
intracoronary wire, and the duration of the inflation.
References
© 1998 American Heart Association, Inc.
Correspondence
Adenosine-Induced Preconditioning of Human Myocardium?
Response
20% of the patients exhibited a
modest increase in blood flow velocity at the end of the second
inflation compared with the first inflation, and again, this increase
did not correlate either with the changes in ST-segment shifts or with
the severity of chest pain. Using a similar technique, Kyriakidis et
al5 found that only 30% of the patients
exhibited progressive collateral recruitment after the first inflation.
It should be noted that the blood flow velocity changes in the
contralateral coronary artery have been shown to be a reliable
index of collateral perfusion during PTCA and to be more accurate than
other indexes, such as measurements of occlusion pressure through the
balloon catheter or coronary angiography. 20% to 50% of the
patients.3 4 5 6 If the increased tolerance to
ischemia observed during subsequent balloon inflations were due
solely to collateral recruitment, then one would expect this phenomenon
to occur only in a minority of the patients. Instead, our
study,7 as well as many other studies (reviewed
in Reference 2), have demonstrated increased tolerance to
ischemia in most or even all of the patients. In addition, this
increased tolerance to ischemia during subsequent inflations
can be abolished by pharmacological manipulations, such as
glibenclamide8 and adenosine receptor
antagonists.9 10 If the mechanism
responsible for this increased tolerance to ischemia were
solely collateral recruitment, it seems unlikely that glibenclamide and
adenosine antagonists would block it.
-adrenergic receptors in ischemia
preconditioning. Circulation. 1997;96:2171–2177.
This article has been cited by other articles:
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  A. Barrier, N. Olaya, F. Chiappini, F. Roser, O. Scatton, C. Artus, B. Franc, S. Dudoit, A. Flahault, B. Debuire, et al. Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion FASEB J, October 1, 2005; 19(12): 1617 - 1626. [Abstract] [Full Text] [PDF]
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 M. A. Leesar, M. F. Stoddard, S. Manchikalapudi, and R. Bolli Bradykinin-induced preconditioning in patients undergoing coronary angioplasty J. Am. Coll. Cardiol., September 1, 1999; 34(3): 639 - 650. [Abstract] [Full Text] [PDF]
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