(Circulation. 1995;92:389-394.)
© 1995 American Heart Association, Inc.
Articles |
Can Ischemic Preconditioning Ensure Optimal Myocardial Protection When Delivery of Cardioplegia Is Impaired?
From the Department of Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London, UK.
Correspondence to Manuel Galiñanes, MD, PhD, Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
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Abstract |
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Background Ischemic preconditioning is a potent protective intervention that is effective in all species studied. We have previously shown it to be as effective as cardioplegia; however, we have also shown that their combined use does not afford greater protection than the use of either alone. In the present study we investigated whether coincident ischemic preconditioning could compensate for inadequate cardioplegic protection when the delivery of cardioplegia was impaired, such as occurs in the presence of severe coronary stenosis or occlusion.
Methods and Results Isolated rat hearts were subjected to 30 minutes of global ischemia followed by 40 minutes of reperfusion. Four groups of hearts (n=12 per group) were studied: group 1, controls (no intervention); group 2, cardioplegia administered to hearts with a proximally occluded coronary artery; group 3, ischemic preconditioning applied before ischemia; and group 4, ischemic preconditioning and cardioplegia given in combination to hearts with a proximally occluded coronary artery. The postischemic recovery of left ventricular (LV) developed pressure (LVDP), expressed as a percentage of preischemic values, was significantly greater (P<.05) in preconditioned hearts (64±3%) than in control hearts (24±4%) or hearts treated with suboptimal cardioplegia (43±5%). Hearts with preconditioning plus cardioplegia recovered to an extent similar to that seen with preconditioning alone (59±2%). LV end-diastolic pressure was greater in control hearts (58±4 mm Hg) than in hearts with cardioplegia (41±4 mm Hg; P<.05 versus group 1) despite the incomplete delivery of the cardioplegia; the best protection was observed in preconditioned hearts and hearts with preconditioning plus cardioplegia (24±1 and 26±2 mm Hg, respectively; P<.05 versus groups 1 and 2).
Conclusions When the delivery of cardioplegia was impaired, myocardial protection (postischemic LVDP) was better served by ischemic preconditioning. Under the same conditions, the combination of cardioplegia plus preconditioning afforded superior protection compared with cardioplegia alone. These results may be of clinical interest since most patients who undergo surgery for ischemic heart disease suffer from severe coronary artery lesions that can prevent the adequate delivery of cardioplegia.
Key Words: cardioplegia • ischemia • reperfusion • occlusion
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Ischemic preconditioning has been shown to be capable of limiting infarct size,1 2 reducing the severity of ventricular arrhythmias during ischemia and reperfusion,3 4 and improving the postischemic recovery of cardiac function.5 6 7 8 This appears to apply to all species studied, including humans.9 Recently, preconditioning has been advocated as an alternative to conventional cardioplegia to protect the heart during surgery.10 Although there is some preliminary evidence of its applicability,9 a definite role for the procedure in surgery on the human heart has yet to be established. However, rather than advocating the replacement of cardioplegia with preconditioning, it might be argued that their combined used could be particularly effective. In this connection, we have demonstrated10 that, although ischemic preconditioning improved the postischemic recovery of contractile function to a degree similar to cardioplegia, their combined use did not improve recovery beyond that seen with either intervention alone. On the basis of such studies, it might be concluded that the protection afforded by cardioplegia and preconditioning is not additive and that there is no argument for their combined use. However, most patients who undergo surgery for ischemic heart disease suffer from severe coronary artery stenoses that can impair the delivery and distribution of cardioplegia to the most vulnerable tissue.11 12 13 14 Under such conditions, it is possible that preconditioning may be a beneficial adjunct to cardioplegia and that it may compensate for the loss of protection.
Although the problems caused by the maldistribution of cardioplegia in the presence of critical coronary stenosis may be reduced by infusion of the cardioplegic solution through the coronary sinus,15 16 17 18 retrograde infusion has problems of its own. Thus, retrograde infusion has been shown to result in less flow to the posterior left ventricular (LV) septum and right ventricular (RV) free wall,19 and its ability to protect the RV and all areas of the LV has been questioned.20 It has also been suggested that retrograde infusion may damage the coronary sinus21 and that the vasculature may be injured if the infusion pressure is high.17 22 Therefore, ischemic preconditioning may be a safe and simple adjunctive method of protection.
In the present study, we used the rat heart to investigate whether ischemic preconditioning affords a greater degree of cardiac protection than antegrade cardioplegia under conditions in which the distribution of cardioplegia is impaired and whether the combination of the two results in better protection than the use of cardioplegia alone.
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Methods |
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Animals
Male Wistar rats weighing 250 to 300 g were used. All animals received appropriate care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1987).
Experimental Preparation
Rats were anesthetized with
pentobarbital (60 mg/kg IP),
the right femoral vein was exposed, and heparin (1000 IU/kg) was
administered. The chest was opened and the heart was excised and placed
in cold (4°C) saline. The aorta was then rapidly cannulated and each
heart was perfused (75 mm Hg) aerobically with the Langendorff method
at 37°C for 20 minutes with oxygenated perfusion fluid
(solution, in mmol/L: glucose 11.1, NaCl 118.5, KCl 4.8,
MgSO4 1.2, KH2PO4 1.2,
NaHCO3 25.0, CaCl2 1.4 at pH 7.4 when gassed
with 95% O2 plus 5% CO2). In some study
groups, hearts received a 2-minute infusion (45 mm Hg) of the St
Thomas' cardioplegic solution (solution, in mmol/L: NaCl 110.0,
KCl 16.0, MgCl2 16.0, CaCl2 1.2,
NaHCO3 10.0 at pH 7.8) immediately before ischemia.
All hearts were paced via the right atrium at 400 beats per min (bpm)
during the preischemic and postischemic periods
and during the first 2 minutes of ischemia. During the
preischemic period of aerobic perfusion, a balloon was
introduced into the LV and inflated to achieve a constant LV
end-diastolic pressure (LVEDP) of 4 mm Hg; this volume
was kept constant until the end of the experiment when the inflation
was again adjusted to achieve an LVEDP of 4 mm Hg. This was necessary
so that preischemic and postischemic cardiac
function might be compared under identical loading conditions. The
balloon was used to measure peak systolic pressure, LVEDP, and LV
developed pressure (LVDP). Coronary flow before and after
ischemia was measured with an in-line electromagnetic
flowmeter (Transonic Systems Inc). At the end of the experiment 4 mL of
1% fluorescein was infused into the coronary
arteries for the assessment of the distribution of myocardial flow (see
below).
Experimental Time Course and Study Groups
After excision,
hearts were aerobically perfused for 20 minutes.
They were then subjected to 30 minutes of normothermic
global ischemia followed by 40 minutes of reperfusion. Four
groups of hearts (n=12 per group) were studied (Fig 1
):
group 1, controls with unprotected ischemia (no intervention);
group 2, hearts in which cardioplegia was administered for 2 minutes
before ischemia; group 3, hearts in which ischemic
preconditioning (3 minutes of ischemia followed by 3 minutes of
reperfusion then 5 minutes of ischemia followed by 5 minutes of
reperfusion) was applied before the 30-minute period of
ischemia; and group 4, hearts in which ischemic
preconditioning and cardioplegia were used in combination before the
ischemia. In hearts protected with cardioplegia (groups 2 and
4), the left anterior descending coronary artery (LAD) was
occluded proximally just before the administration of the cardioplegia.
In this way, the cardioplegic solution was prevented from reaching a
substantial area of myocardium. The arterial
occlusion was released immediately before reperfusion.
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Postischemic Assessment of Flow
Distribution
The distribution of myocardial flow was assessed at the
end of
the 40-minute period of reperfusion to ensure that the coronary
occlusion had not resulted in permanent structural lesions that could
compromise the reperfusion.
At the end of the 40-minute period of reperfusion, 4 mL of 1% fluorescein (Sigma Chemical Co) was infused (75 mm Hg) at 37°C. Hearts were then frozen and cut into 10 transverse sections (1-mm thick), and the RV was separated and excluded from the rest of the heart. The remaining sections were then videotaped with a CCD camera (Pulnix America, Inc) in a dark room with standard conditions of illumination (long-wave ultraviolet light) and at a fixed focal distance and magnification. Analog images were digitized and analyzed for density of fluorescence (with NIH IMAGE software). Preliminary calibration of the system had been achieved by infusing decreasing concentrations of fluorescein into aerobically perfused hearts to obtain a correlation between density of fluorescence and amount of fluorescein. Gray scale density was divided into three bands: (1) areas with a density of 1 to 149 (amount of fluorescein >50%) were classified as having good flow, (2) areas with a density of 150 to 170 (amount of fluorescein 5% to 50%) as having low flow, and (3) areas with a density of 171 to 256 (amount of fluorescein <5%) as having no-reflow. The number of pixels coming from a single heart (10 slices, 1-mm thick) was added to each gray scale band (1 to 149, 150 to 170, and 171 to 256), and the values within each group were averaged. For comparative purposes nonischemic, aerobically perfused hearts (n=8) were infused with the same amount of fluorescein and subjected to an identical protocol for the assessment of distribution of flow.
Expression of Results and Statistical
Analysis
LVDP (in mm Hg) was calculated as the difference between peak
systolic pressure and LVEDP. The amount of good flow, low flow, and
no-reflow, corresponding to the number of pixels in each band, was
expressed as a percentage of the total number of pixels in the heart.
All results were expressed as mean±SEM in absolute values or
percentage of the preischemic values. An ANOVA was used;
after a significant F value was obtained, any comparisons
between the four study groups were carried out with the Newman-Keuls
test. A difference was considered statistically significant when
P<.05.
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Results |
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All hearts that were entered into the study were included in the analysis. The mean preischemic values for LVDP (128±2, 131±3, 133±4, and 126±3 mm Hg in groups 1, 2, 3, and 4, respectively) and coronary flow (12.2±0.5, 11.4±0.5, 11.9±0.5, and 11.5±0.5 mL/min in groups 1, 2, 3, and 4, respectively) were similar in all groups.
Ischemic Contracture
As shown in Fig 2, the
time to peak contracture
during unmodified ischemia was 14.5±0.5 minutes. This was
delayed by the administration of cardioplegia (to 21.8±1.4 minutes,
P<.05). In contrast, in the preconditioned group and the
group with preconditioning plus cardioplegia the time to peak
contracture was significantly shortened (to 6.8±0.3 and 9.4±0.8
minutes, respectively; P<.05). The magnitude of the peak
contracture was greater in the preconditioned and preconditioning
plus cardioplegia groups (103±2 and 96±3 mm Hg, respectively)
than in either the control hearts (75±2 mm Hg, P<.05) or
the hearts protected with cardioplegia alone (70±3 mm Hg,
P<.05). However, the extent of contracture at the end of
the 30-minute period of ischemia was similar in all groups
(54±1, 59±3, 52±1, and 59±2 mm Hg in groups 1, 2,
3, and 4,
respectively; P=NS).
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P<.05 vs the group receiving cardioplegia.
Postischemic Recovery of LVDP
As shown in Fig
2
, postischemic LVDP (identified as
the shaded area) was similar in all groups during the first 15 minutes
of reperfusion. Thereafter, it improved relatively little in control
hearts. Hearts protected with cardioplegia alone tended to recover
better than control hearts, but the difference failed to achieve
statistical significance. In contrast, a progressive and significantly
greater recovery was observed in hearts protected with preconditioning
alone or in hearts receiving preconditioning plus cardioplegia. Thus,
after 20 minutes of reperfusion, the recovery of LVDP was only 16±3
mm Hg in control hearts and 34±9 mm Hg with cardioplegia alone
(P=NS), whereas the recovery with preconditioning alone and
preconditioning plus cardioplegia was 51±7 and 49±8 mm Hg,
respectively (P<.05 versus control). This improved recovery
was even greater for the rest of the reperfusion period. Fig 3A
shows the final postischemic recovery of
LVDP in all groups.
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Postischemic Recovery of LVEDP
As shown in Fig
2, LVEDP was high in all groups at the onset of
reperfusion, with the highest value recorded in the control group
(107±4 mm Hg). This slowly fell to 58±4 mm Hg over the ensuing
40
minutes of reperfusion. In hearts protected with cardioplegia, LVEDP at
the onset of reperfusion (88±4 mm Hg) was significantly lower than in
controls (P<.05 at all times during reperfusion). By the
end of reperfusion, LVEDP had fallen to 41±4 mm Hg
(P<.05). As with LVDP, the best protection of LVEDP was
observed in the preconditioned hearts (in which LVEDP at the onset of
reperfusion was 67±2 mm Hg and after reperfusion 24±1 mm Hg;
P<.05) and in hearts with preconditioning plus cardioplegia
(in which LVEDP at the beginning and end of reperfusion was 72±3 and
26±2 mm Hg, respectively; P<.05). In both preconditioned
groups, LVEDP (which progressively decreased during the reperfusion
period in all groups) at all times was significantly better than in
either the control group or the cardioplegia-alone group. However,
there were no significant differences between groups 3 and 4.
Postischemic Recovery of Coronary
Flow
As shown in Fig 3B, the postischemic recovery of
coronary flow at the end of the reperfusion period was only
58±6% in control hearts. In preconditioned hearts and in hearts with
preconditioning plus cardioplegia, it was increased to 80±4% and
75±2%, respectively (P<.05). Hearts protected with
cardioplegia alone showed an intermediate value (69±3%) that did not
differ significantly from those of either the control group or the
preconditioned group.
Distribution of Myocardial Flow
The results given in the
Table show that at the end
of the reperfusion period the distribution of flow was similar in all
study groups and that the values for the areas with good flow, low
flow, and no-reflow were not significantly different from those
obtained in the aerobic control hearts. This confirms that after 30
minutes of ischemia and 40 minutes of reperfusion there was no
evidence of no-reflow in any group and that the temporary occlusion
of the LAD in groups 2 and 4 had not resulted in permanent structural
changes that might have compromised reperfusion. The absence of
no-reflow in any of the study groups may suggest that there were no
areas of myocardial necrosis present. However, 40 minutes of
reperfusion was a relatively short period, and it may be that if
reperfused for a longer period, areas of myocardial necrosis might have
developed. In this connection, it has been shown (G. Baxter, personal
communication, 1995) that in an identical experimental model with
similar ischemic conditions that areas of myocardial necrosis
are not observed until after 2 hours of continuous reperfusion.
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Discussion |
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The present study has demonstrated that in the presence of a coronary occlusion that has impaired the delivery of cardioplegia to some parts of the heart, ischemic preconditioning afforded a greater protection than did antegrade cardioplegia alone. Furthermore, the combination of preconditioning and cardioplegia afforded greater protection than that provided by cardioplegia alone. This finding contrasts with those of earlier studies10 in which the combination of cardioplegia and preconditioning had no additive effect. However, in that study, adequate cardioplegia was delivered to all regions of the heart. A number of aspects of the present study are discussed below.
Should Preconditioning be Advocated as an Alternative or as an
Adjunct to Cardioplegia?
On the basis of the present study alone, one
might argue that
preconditioning should replace cardioplegia in all those surgical
patients (ie, the majority) in whom the delivery of cardioplegia to
some area of the heart is suspected of being impaired. However, the
proposal would be premature because (1) evidence for the effectiveness
of preconditioning as a means of improving postischemic
function in the human heart undergoing surgery is not yet available,
(2) little is known about mechanisms of preconditioning or the
conditions (number and duration of cycles of ischemia) required
to achieve protection in the human heart, and (3) some aspects of
preconditioning, particularly its paradoxical effect on the
diastolic state during ischemia, appear at first
sight to be unfavorable.
Protection of the heart during coronary artery surgery is still a matter of major concern, especially when vessels are occluded or severely stenosed. It has been well established that when the heart is diseased antegrade cardioplegia may fail to give adequate protection to all its regions.11 12 13 14 15 16 17 18 As a consequence, these hearts exhibit temperature11 12 13 14 and pH23 gradients, both of which contribute to further tissue injury. Retrograde cardioplegia has been proposed as an obvious alternative or additive to antegrade cardioplegia; certainly, it provides a means of delivering cardioplegia to regions of the heart that might be deprived of the solution if it were delivered in an antegrade manner. However, although retrograde cardioplegia is widely accepted in clinical practice, it has several potential problems. Thus, it has been reported that retrograde cardioplegia may not give adequate protection to the RV or provide uniform protection to all areas of the LV.15 16 17 18 In addition, retrograde infusion might injure the coronary sinus through the introduction and inflation of the infusion catheter.21 Likewise, cardioplegia infused at excessively high pressures may damage the coronary vasculature.17 22 Finally, the application of retrograde cardioplegia may occasionally be difficult and time-consuming; on the strength of this alone, ischemic preconditioning would appear to provide a safe and simple means of achieving optimal protection.
In the endeavor to improve cardioprotection, particularly in the diseased heart, it would seem prudent to be conservative. To this end, we need to (1) study further the potential for the use of preconditioning as an adjunct to existing forms of protection, (2) overcome the existing problems with the delivery of cardioplegia (eg, with retrograde administration), and (3) explore other forms of protection.
In considering alternative approaches to both cardioplegia and preconditioning, aortic cross-clamp fibrillation has been and still is being used successfully by some surgeons for the correction of ischemic coronary artery disease.24 25 With this technique, each coronary artery anastomosis is performed during a brief (<10- to 12-minutes) period of ischemia followed by another brief period of reperfusion (<10 to 12 minutes during which the proximal anastomosis is constructed). However, it has not escaped the attention of surgeons that this procedure in many ways mimics an ischemic preconditioning protocol. It may well be that for many years surgeons have unwittingly been successfully preconditioning hearts with their use of short periods of ischemia during coronary bypass surgery.
Mechanisms of Protection of Ischemic
Preconditioning
While the protective effect of cardioplegia comes from
rapidly
inducing electromechanical arrest (and, as a consequence, conserving
tissue high-energy phosphates) and slowing (by hypothermia)
deleterious ischemia-induced reactions,26 the
mechanism underlying ischemic preconditioning remains elusive.
There is, however, growing evidence that stimulation of membrane
receptors such as A1 and A3 adenosine
receptors,27 28 29 30
ATP-sensitive potassium
channels,31 32 
1-adrenergic
receptors,8 33 34 or muscarinic
receptors35 36 may be in some way involved in
ischemic preconditioning and that this protection may be
mediated through activation of protein kinase
C.33 37 38 39
Evidence also shows that preconditioning can influence the rate of
decline of ATP during ischemia and effectively lessen the
degree of acidosis that occurs in the ischemic
heart.6 7 40 Indeed, we have
shown40 that in
this respect preconditioning is far more protective than
cardioplegia.
In seeking to define the mechanisms underlying preconditioning, many investigators have shown that ischemic preconditioning can be mimicked by exchanging the preconditioning cycle for various agents such as adenosine, epinephrine, or bradykinin.8 27 28 29 30 33 34 41 This raises the interesting possibility that pharmacological preconditioning may prove to be valuable in cardiac surgery since the time lost with ischemic preconditioning could be avoided. While this might apply to hearts without severe coronary artery stenoses, it may prove impractical in the presence of severe lesions for the very same reasons that limit the delivery of cardioplegia.
Preconditioning and Contracture
Using a variety of
experimental models, we and
others6 42 43 have observed the
paradoxical ability of
preconditioning to intensify ischemic contracture. The results
of the present study are not only in agreement with these
observations but they also confirm the striking ability of cardioplegia
to exert the opposite effect and to protect against contracture. The
role of ischemic contracture in preconditioned hearts and its
interpretation clearly need further investigation, and until the
phenomenon is explained, caution should be exercised in advocating the
use of preconditioning in humans.
Postischemic Contractile State and
Coronary Flow
Our study has shown that despite an increase in
diastolic tension during the early stages of
ischemia, preconditioning gave the best recovery during
reperfusion. This observation allows us to speculate that the
beneficial effect of preconditioning could at least in part be exerted
during reperfusion. The study also indicates that the coronary
vasculature (as assessed by the postischemic recovery of
coronary flow) is protected by preconditioning. These results
are in agreement with previous findings from our
laboratory10 and suggest that the protection of
preconditioning may not be exclusive to the cardiac myocyte but may
also benefit other cell types. The better recovery of coronary
flow in preconditioned hearts compared with control hearts, in the
absence of differences in the myocardial distribution of flow (ie, the
lack of no-reflow), may further suggest that the changes in flow are
caused by vascular dysfunction.
Limitations of the Present Study
We of course concede that
the present findings were made in
the rat heart. Moreover, it should be noted that our study was
performed under normothermic conditions; it is therefore
important to ask whether preconditioning is protective in the context
of hypothermic ischemia. In a previous study,44 we
showed that this appears to be the case. Another possible limitation of
the present study may be the use of an isolated heart preparation
that does not possess a collateral circulation (a notable difference
with the clinical situation) and the fact that the hearts were perfused
with a crystalloid solution instead of blood. Thus, before clinical
studies are initiated, it would be advisable to confirm these results
in other blood-perfused, in vivo preparations.
Conclusions
The present study has demonstrated that under
conditions in
which the antegrade delivery of cardioplegia was impaired,
ischemic preconditioning afforded greater myocardial protection
than cardioplegia. These results may be of clinical interest since most
patients who are subjected to surgery for ischemic heart
disease have severe coronary artery lesions that may preclude
the uniform distribution of cardioplegia and thus the adequate
protection of all areas of myocardium. While
preconditioning may have a role to play in these conditions, a number
of important questions remain to be resolved. In particular, it would
be interesting to examine whether the protective effect afforded by
preconditioning also applies to the chronically ischemic
myocardium in the presence of various degrees of
coronary stenosis (which would allow some delivery of
cardioplegia to the myocardium supplied by the
stenotic vessel) rather than just to occluded arteries (with
little or no distal distribution of cardioplegia).
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Acknowledgments |
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This work was supported in part by grants from STRUTH, the British Heart Foundation, and the Joint Research Board of St Bartholomew's Hospital (9G46).
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