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Ann Thorac Surg 2000;70:590-594
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Is adenosine preconditioning truly cardioprotective in coronary artery bypass surgery?

^a Department of Cardiovascular Surgery, Hôpital Bichat, Paris, France
^b Department of Biochemistry, Hôpital Lariboisiere, Paris, France
^c Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan

Address reprint requests to Dr Menasché, Department of Cardiovascular Surgery, Hôpital Bichat, 46, rue Henri-Huchard, 75877 Paris Cedex 18, France

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. The large number of experimental studies showing that adenosine "turns on" the protein kinase C (PKC)-mediated pathway that accounts for the cardioprotection conferred by ischemic preconditioning contrasts with the scarcity of clinical data documenting the preconditioning-like protective effect of adenosine during cardiac operations on humans.

Methods. Forty-five patients undergoing coronary artery bypass were randomized to receive, after the onset of cardiopulmonary bypass, a 5-minute infusion of adenosine (140 µg · kg^-1 · min^-1) followed by 10 minutes of washout before cardioplegic arrest (n = 23) or an equivalent period (15 minutes) of prearrest drug-free bypass (controls, n = 22). Outcome measurements included troponin I release over the first 48 postoperative hours and activity of ecto-5'-nucleotidase, an admitted reporter of PKC activation, as assessed on right atrial biopsies taken before bypass and at the end of the preconditioning protocol (or after 15 minutes of bypass in control patients).

Results. Aortic cross-clamping times were not different between the two groups. Likewise, prebypass values of ecto-5'-nucleotidase (nanomoles/mg protein per minute) were similar in control (3.14 ± 1.02) and adenosine-treated (2.66 ± 1.08) patients. They subsequently remained unchanged in control patients (3.87 ± 1.65) whereas they significantly increased after adenosine preconditioning (4.47 ± 1.96, p < 0.001 versus base line values). However, peak postoperative values of troponin I (µg/L) were not significantly different between control (4.8 ± 2.8) and adenosine-preconditioned patients (5.9 ± 6.6) nor were the areas under the curve. There were no adverse effects related to adenosine.

Conclusions. Adenosine, given at a clinically safe dose, can turn on the PKC-mediated signaling pathway involved in preconditioning but this biochemical event does not translate into reduced cell necrosis after coronary artery surgery, suggesting that a preconditioning-like protocol may not be the best suited for exploiting the otherwise well-documented cardioprotective effetcs of adenosine.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
There is now a large body of experimental evidence that ischemic preconditioning is one of the most effective means of reducing myocardial cellular necrosis. As such, its implementation during cardiac operations might represent a useful adjunct to current techniques of myocardial protection, in particular in high-risk patients. In this setting, however, it is counter-appealing to use ischemia as the preconditioning stimulus [1–3], hence the extensive research targeted at identifying clinically usable compounds that could pharmacologically mimick the cardioprotective effects of classic ischemic preconditioning.

There is compelling evidence that the preconditioning signal activates various membrane receptors that trigger a signaling pathway leading to activation of several kinases, in particular protein kinase C (PKC) [4, 5] and the subsequent opening of adenosine triphosphate-dependent potassium channels, possibly at the mito-chondrial level [6, 7]. Several experimental studies have now demonstrated that A₁ and A₃ adenosine receptors are involved in the endogenous cardioprotective response as their activation reproduces the infarct-limiting effect of ischemic preconditioning whereas protection is lost when the receptors are blocked [8]. In contrast, human data remain scarce and only a few studies have investigated the effects of adenosine given either before cardiopulmonary bypass [9] or as an additive to blood cardioplegia [10, 11]. The present study was therefore designed to assess the effects of adenosine preconditioning in patients undergoing coronary artery bypass grafting with the two more specific objectives of determining (1) whether administration of the drug was mechanistically linked to the triggering of the PKC-mediated preconditioning pathway, and (2) whether these biochemical events correlated with enhanced cardioprotection.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Protocol
Forty-five patients undergoing elective coronary artery bypass grafting were prospectively studied. The conduct of anesthesia and operation was similar in all patients. For anesthesia, fentanyl, flunitrazepam, and pancuronium were used in a standard combination. As isoflurane may exert a preconditioning-like effect through opening of adenosine triphosphate-sensitive potassium channels [12], care was taken to avoid its administration until the second right atrial biopsy was taken (see below).

The heart was approached through a median sternotomy. Following heparinization, cardiopulmonary bypass was established with a single two-stage right atrial cannula and an ascending aortic cannula and the left ventricle was vented through the right superior pulmonary vein. The extracorporeal circuit consisted of a nonpulsatile roller pump, a membrane oxygenator and a 20-µm arterial line filter. Once bypass was run at full flow (2.2 L · min^-1 · m^-2 of body area) with the heart totally decompressed, patients were randomly assigned to the control or preconditioning group.

Preconditioning was achieved with a 5-minute infusion of adenosine (Krenosin; Sanofi Winthrop, Gentilly, France) at the dose of 140 µg/kg of body weight per minute. The infusion was made through a central venous catheter and followed by 10 minutes of washout before aortic cross-clamping. Control patients underwent a time-matched (15 minutes) period of adenosine-free CPB. After aortic cross-clamping, myocardial protection was provided by minimally diluted blood cardioplegia delivered retrogradely through the coronary sinus in a continuous fashion, as previously described [13]. The core temperature was allowed to drift spontaneously to 33°C to 34°C and blood cardioplegia was administered at this same tepid temperature.

End points
The assessment of results was made on blood markers of myocardial necrosis and tissue markers of PKC activation. To detect perioperative myocardial necrosis, blood levels of troponin I were serially measured by the Stratus II automated two-site fluorometric enzyme immunoassay (Dade Diagnostika, Munich, Germany) after induction of anesthesia, upon arrival in the intensive care unit, and at 6 hours, 1 day and 2 days postoperatively. To detect PKC activation, right atrial biopsies were taken before bypass and then either at the end of the 15-minute preconditioning cycle in adenosine-treated patients or after an equivalent pump time in controls. Tissue specimens were frozen and stored under liquid nitrogen and the ecto-5'-nucleotidase and cytosolic 5'-nucleotidase activity were then measured as previously described [14]. In brief, the myocardium was separated into its membrane (ectosolic [ecto]) and cytosolic (cyto) fractions as follows: The tissue was homogenized for 5 minutes in 10 vol of ice-cold 10 mmol/L N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-potassium hydroxyde (HEPES-KOH) buffer (pH 7.4) containing 0.25 mol/L sucrose, 1 mmol/L MgCl₂, and 1 mmol/L mercaptoethanol at 0°C. The crude homogenate was strained through a double-layer nylon sieve and homogenized again for 1 minute. To prepare a crude membrane fraction, part of the homogenate was centrifuged at 1,000g for 10 minutes. The resulting pellet was washed three times and resuspended in the HEPES-KOH buffer. To prepare the cytosolic fraction, the remaining part of the homogenate was first centrifuged at 3,000g for 10 minutes, and the supernatant was centrifuged at 200,000g for 1 hour. The membrane and cytosolic fractions were dialyzed at 4°C for 4 hours against 10 mmol/L HEPES-KOH (pH 7.4) containing 1 mmol/L MgCl₂, 1 mmol/L mercaptoethanol, and 0.01% activated charcoal and were divided into aliquots that were frozen immediately and stored at -80°C. We have previously shown that, with this procedure, the recovery of 5'-nucleotidase activity in the membrane fraction is 97%. 5[prime]-nucleotidase activity was assessed by the enzymatic assay technique and is reported as units of nanomoles per milligram of protein per minute. Protein concentration was measured by the method of Lowry and coworkers [15], using bovine serum albumin as standard.

Additional outcome analysis included hospital mortality, postoperative complications (in particular the occurrence of Q-wave infarct and the need for inotropic and mechanical support), and any side effects during adenosine infusion. All postoperative electrocardiograms were reviewed by a cardiologist blinded to the patient group.

Statistics
Release of troponin I (ng · mL^-1 · h^-1) over the first postoperative 48 hours was calculated as the area under the curve using a curve-fitting application that generated a series of rectangles between consecutive points on the curve. The area of these rectangles was then summated. A two-factor repeated-measures analysis of variance (ANOVA) was also used for comparing postischemic enzyme values over time between the two groups. Data on 5'-nucleotidase activity were compared with paired and unpaired two-tailed t tests. Significance was set at the 0.05 level. Results are reported as mean ± SD.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
The clinical profiles and intraoperative data of the patients are summarized in Table 1. The two cohorts were similar with respect to all parameters. As shown in Figure 1 , prebypass values for ecto-5'-nucleotidase activity were not different between the two groups. They subsequently remained unchanged in control patients whereas they significantly increased following adenosine preconditioning (p = 0.001 versus base line values). Likewise, base line activities for cyto-5'-nucleotidase were similar in control (7.8 ± 3.4 nanomoles/mg protein per minute) and adenosine-preconditioned (6.6 ± 3.3 nanomoles/mg protein per minute) patients. However, in contrast to the ectosolic fraction, the cytosolic fraction did not change significantly thereafter and, after 15 minutes of bypass, averaged 7.5 ± 3.3 and 6.1 ± 4.1 nanomoles/mg protein per minute in control and adenosine-preconditioned patients, respectively.

View larger version (19K): [in this window] [in a new window]   Fig 1. Effects of adenosine preconditioning on ectosolic activities of 5'-nucleotidase. For each patient, right atrial biopsies were taken before bypass (baseline) and either at the end of the preconditioning (PC) protocol or at a time-matched study point in control patients. Data are expressed as mean values ± SD.

View larger version (20K): [in this window] [in a new window]   Fig 2. Effects of adenosine preconditioning on postoperative troponin I release. Data are expressed as mean values ± SD.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
The two major findings of the present study are (1) that prearrest administration of adenosine at a clinically safe dose "turns on" the preconditioning pathway mediated by activation of PKC, and that (2) this biochemical event does not correlate with enhanced cardioprotection, at least on the basis of clinicallly relevant markers.

According to the current scheme, adenosine receptors are among those whose activation triggers the preconditioning pathway which then involves upregulation of several kinases, in particular PKC [4, 5], and, ultimately, opening of adenosine-triphosphate sensitive mitochondrial potassium channels [6, 7]. The mechanism by which opening of these channels elicits cardioprotection is not yet fully elucidated but could involve reduction of calcium overload or better control of mitochondrial volume and energetics, or both [16]. However, the clinical relevance of these findings still remains uncertain.

In patients undergoing coronary artery angioplasty procedures, two studies [17, 18] have reported the benefits of intracoronarily injected adenosine, as assessed by a reduction in ST-segment shift during balloon inflations. Conversely, in the surgical setting, the results are more conflicting. Thus, Lee and coworkers [9] have studied 7 patients to whom adenosine was given for 10 minutes followed by 5 minutes of washout before the onset of CPB. Postbypass function was found to be improved compared with control patients, and correlated with a decreased release of creatine kinase. In contrast, two double-blind, randomized, placebo-controlled phase II studies of adenosine in blood cardioplegia in 328 patients [10] failed to disclose any benefit of the drug, which, regardless of the dose (15 µmol/L, 50 µmol/L, 100 µmol/L) was unable to improve the primary efficacy outcome (which consisted of a composite end point including all-cause 30-day mortality, myocardial infarction by enzymatic analysis, and low output syndrome). In another phase II multicenter trial [11], the benefits of high-dose adenosine (2 mmol/L) added to blood cardioplegia (in addition to a 10-minute pretreatment and a 15-minute reperfusion infusion) could only be demonstrated by using a composite outcome of high-dose dopamine, epinephrine use, insertion of an intraaortic balloon, myocardial infarction and death. However, the trial failed to demonstrate a reduction in dopamine utilization or overall inotropic use, which were two of the proposed primary end points.

In the present study, administration of adenosine before aortic cross-clamping likely caused PKC activation, as reflected by increased right atrial levels of ecto-5'-nucleotidase. Although the correlation between increased levels of ecto-5'-nucleotidase and enhanced cardioprotection remains controversial [20, 21], the fact that this enzyme (which degrades adenosine monophospate into adenosine) is one of the substrates phosphorylated by PKC [22] leads to its consideration as a surrogate marker of PKC activation. In our study, however, elevated myocardial levels of ecto-5'-nucleotidase did not correlate with better tissue protection against surgically induced necrosis, at least on the basis of postoperative values of troponin I.

Several hypotheses can be raised to account for the lack of adenosine-induced enhancement of cardioprotection reported in the present study. A first possibility would be that adenosine has little, if any, cardioprotective effect in the human heart. This assumption is not supported, first, by in vitro studies showing that adenosine can protect human ventricular cardiomyocytes [22] and right atrial trabeculae [23] exposed to hypoxia, and second, by the previously mentioned reduction in ischemic symptoms reported for patients receiving intracoronary adenosine during angioplasty [17, 18].

A second hypothesis is that we used inadequate doses of adenosine. For safety concerns, the dosage regimen (140 µg · kg^-1 · min^-1 given over 5 minutes, which roughly represented a total load of 60 mg per patient) was similar to that reported to be well tolerated in a large multicenter trial (9,256 patients) that assessed the effects of adenosine in conjunction with radionuclide perfusion imaging [24]. We acknowledge that in the positive study of Lee and associates [9], higher doses (up to 350 µg · kg^-1 · min^-1) have been used, at the cost, however, of hypotensive episodes leading to reduce the infusion rate in some patients. Such was not the case in the phase II trial reported by Cohen and coworkers [10] where there was no dose-dependent benefit of adenosine and even a trend for the highest dose (100 µmol/L, ie, 40 mg, a dose still inferior to that used in our patients) to be associated with the poorest outcomes.

Another possible explanation for our failure to demonstrate an adenosine-induced enhancement of cardioprotection could be related to the protocol of drug administration. To comply with a preconditioning protocol, the infusion of adenosine was followed by 10 minutes of washout. However, in a rabbit model of global ischemia, Lasley and coworkers [25] have shown that for pharmacologic activation of adenosine A₁ receptors to elicit protection, the agonist needed to be given until the onset of the ischemic period (ie, without preischemic washout). The same group [26] has also reported that adenosine given according to the same protocol as in our study (140 µg · kg^-1 · min^-1 given over 5 minutes followed by a 10-minute washout before the prolonged ischemia) only resulted in a transient increase in interstitial fluid adenosine levels that resolved more rapidly than after classic ischemic preconditioning. In line with these observations, the successful clinical study of Lee and associates [9] involved a longer infusion to washout ratio (10 minutes/5 minutes) than in the present study and the salutary effects of adenosine on composite outcome analysis reported in one of the phase II surgical trials [11] also required a protracted exposure to the drug (which was given before, during, and after cardioplegic arrest).

Waning of protection could also have been facilitated by the fact that adenosine was not injected directly into the coronary arteries, and that, given its short half-life, might have prevented its presence in sufficiently high concentrations in the myocardium. Nevertheless, to correct for this factor, we used an infusion rate so that the total amount of adenosine systemically delivered was fourfold higher than that calculated from experimental data to be effective for preconditioning a human heart [18]. Furthermore, our findings of elevated levels of ecto-5'-nucleotidase in right atrial biopsies of treated patients suggests that the drug was yet able to reach its target tissue and that the preconditioning pathway was likely turned on. A last hypothesis is that increased levels of ecto-5'-nucleotidase only reflected global PKC activation, which did not necessarily involve upregulation of the isoforms specifically relevant to cardioprotection [22].

We finally acknowledge that, in addition to its infarct-limiting effect, adenosine can also limit postischemic stunning [9]. The lack of systematic postoperative hemodynamic assessment does not allow us to rule out that, although it did not reduce enzyme release, adenosine preconditioning improved functional recovery but the crude comparison of inotropic requirements between control and adenosine-treated patients does not support this hypothesis. Furthermore, although differences in postoperative enzyme release were not significantly different between the two groups (possibly because of the wide scattering of data), there was an unexpected trend for adenosine-preconditioned patients to release greater amounts of troponin I after surgery. We do not have a clear explanation for this finding but one possibility is that adenosine did cause some coronary steal [27] leading to worsen ischemia in the myocardial areas supplied by the most diseased arteries. This hypothesis would be consistent with our previous observations [1] that when an ischemic-type stimulus is applied before cardioplegic arrest, the deleterious effects of ischemia outweigh the putative benefits of the preconditioning intervention.

In conclusion, administration of adenosine according to a clinically relevant preconditioning protocol did not result in reduced intraoperative cell necrosis or improved patient outcomes. Changes in the dose and timing of administration of the drug could be a means of enhancing cardioprotection but this is likely to require adenosine analogues, currently in a developmental stage, that can specifically activate cardiomyocyte-bound receptors without causing detrimental vascular effects. An alternate strategy is to target the end-effector of the preconditioning pathway, an approach supported by the encouraging results that we have recently reported with a putative potassium channel opener (the inhalational anesthetic isoflurane) in patients undergoing coronary artery bypass operations [28]. Regardless of the selected compound, these cardioprotective interventions should be electively tested in high-risk patients, as the present study confirms that the efficacy of continuous retrograde tepid blood cardiopegia makes it difficult to demonstrate that low- or medium-risk patients really benefit from additional intraoperative protective measures.19

	Acknowledgments

 
Supported in part by a grant from the European Commission, Biomed-2 Concerted Action no. 95-0838, "The New Ischemic Syndromes."

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Philippe Menasché Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Belhomme, D. Articles by Menasché, P. Search for Related Content PubMed PubMed Citation Articles by Belhomme, D. Articles by Menasché, P.