Skip Navigation

Cardiovascular Research 2002 53(1):175-180; doi:10.1016/S0008-6363(01)00435-7
© 2002 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Teoh, L.K.K.
Right arrow Articles by Yellon, D.M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Teoh, L.K.K.
Right arrow Articles by Yellon, D.M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2001, European Society of Cardiology

The effect of preconditioning (ischemic and pharmacological) on myocardial necrosis following coronary artery bypass graft surgery

L.K.K. Teoha, R. Grantb, J.A. Hulfb, W.B. Pugsleyb,c and D.M. Yellona,*

aThe Hatter Institute for Cardiovascular Studies, Department of Cardiology, UCL Hospitals, Grafton Way, London WC1E 6DB, UK
bThe Department of Cardiothoracic Surgery, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK
cThe Sussex Cardiac Centre, Royal Sussex County Hospital, Brighton, UK

* Corresponding author. Tel.: +44-20-7380-9888; fax: +44-20-7388-5095 hatter-institute{at}ucl.ac.uk

Received 9 May 2001; accepted 8 August 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: Ischemic preconditioning is known to protect the human heart from ischemic injury during coronary artery bypass graft (CABG) surgery but is not practised routinely. Adenosine A1 receptor agonists may confer protection in this setting by mimicking preconditioning. The aim of this study was to compare preconditioning, by ischemia or an adenosine A1 receptor agonist (GR79236X), with an established method of myocardial protection in CABG, namely intermittent cross-clamp fibrillation. Methods: In this prospective double-blind study, 30 CABG patients were randomised to receive: (a) intermittent cross-clamp fibrillation (control), (b) pharmacological preconditioning (GR79236X), or (c) ischemic preconditioning (two 3-min periods of ischemia, each followed by 2 min of reperfusion). Surgery was performed under standardised conditions by one surgeon (WBP). The primary endpoint was cardiac troponin T release. Results: Mean cardiopulmonary bypass time was 91±11.6 (S.D.) min. Mean ischemic time was 33±5.5 (S.D.) min with no inter-group difference. Mean troponin T at 72 h was highest in the control group (1.32±0.99 (S.D.) µg/l), similar in the GR79236X group (1.22±1.22 (S.D.) µg/l; P=0.85) and significantly reduced in the ischemic preconditioning group (0.58±0.40 (S.D.) µg/l; P=0.04). Conclusions: Ischemic preconditioning is superior to the other techniques at limiting myocardial necrosis during CABG. Pharmacological preconditioning may confer some benefit but this was not statistically shown using a specific adenosine A1 agonist (GR79236X).

KEYWORDS Adenosine; Cardiovascular surgery; Preconditioning


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Coronary artery bypass graft (CABG) operations continue to increase in number. Furthermore patients with poorer ventricular function and more diffusely diseased vessels are coming forward for surgery. In this climate, myocardial protection against ischemic injury during surgery must be optimal. Our earlier studies have shown that short bursts of ischemia followed by reperfusion protect the human myocardium against subsequent longer ischemic insults, as evidenced by preservation of myocardial ATP levels [1] and reduction of cardiac troponin T release [2]. Repeated clamping of the aorta to render the heart ischemic may indeed invoke protective preconditioning, but is unlikely to be an acceptable method of myocardial protection to the majority of cardiac surgeons. Pharmacological preconditioning would be far more acceptable. Adenosine [3] and more specifically adenosine A1 receptor activation [4,5] have been implicated as triggers of the preconditioning response. In a number of species, including rabbit, rat and mouse, and in a human isolated atrial trabecula muscle model, the selective A1 agonist, 2-chloro-N6-cyclopentyladenosine (CCPA) has been used to precondition the myocardium against severe ischemia [6–9]. A putative mechanism of action suggests that pharmacological activation of the A1 receptor is the first step in a signal transduction pathway that culminates in opening of the mitochondrial KATP channel, resulting in myocardial protection [10–13].

GR79236X is a selective adenosine A1 receptor agonist [14] conferring cardioprotection in animal models of myocardial infarction [15,16]. In the anaesthetised rabbit [15] and pig [16], significant reduction of myocardial infarct size was obtained by administering GR79236X (3.5 µg/kg) prior to the onset of ischemia. The compound, developed by Glaxo Wellcome, underwent rigorous pre-clinical and safety trials. We obtained quantities of GR79236X (which will not be developed as a prescription drug) and a Medicines Control Agency Product Licence Exemption Certificate for its use in this study.

The aim of this study was to determine whether a selective adenosine A1 agonist could induce pharmacological preconditioning in the setting of CABG surgery and to test its efficacy against ischemic preconditioning and an established method of myocardial protection, namely intermittent cross-clamp fibrillation.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
This investigation conforms to the principles outlined in the Declaration of Helsinki. It received local Ethics Committee approval and was carried out in accordance with the UCL Hospitals NHS Trust guidelines.

2.1 Patient selection
Patients referred for elective CABG surgery with three-vessel coronary artery disease and good left ventricular function (ejection fraction >35%) were approached. Written informed consent was obtained from all patients recruited. Patients over 80 years of age, with unstable angina or significant left main stem disease, or with hepatic, renal or pulmonary disease were excluded. Diabetic patients were also excluded, as were patients taking KATP channel openers (e.g., nicorandil) within 36 h of surgery. Thirty consenting patients were randomised to receive: (a) intermittent cross-clamp fibrillation alone (ICCF), (b) GR79236X plus cross-clamp fibrillation, or (c) ischemic preconditioning (IPC) plus cross-clamp fibrillation, during surgery. Randomisation between ICCF (group a) and GR79236X (group b) was double-blinded, the former receiving a placebo infusion, whilst randomisation to IPC (group c) was on an open basis.

2.2 Surgical methodology
All operations were performed by a single consultant surgeon (WBP). Anaesthetic and cardiopulmonary bypass (CPB) techniques were standardised. One hour before induction of anaesthesia, patients received premedication consisting of morphine 5–10 mg and hyoscine 0.2–0.4 mg i.m. Anaesthesia was induced with midazolam, fentanyl and pancuronium. Isoflurane was not used. Anaesthesia was maintained with a propofol infusion and midazolam, fentanyl and pancuronium were administered as required. Pump flows were adjusted to achieve continuous, non-pulsatile flow of 2.4 l/min per m2 at 37°C. The perfusion pressures were regulated to maintain a mean pressure between 60 and 100 mmHg, if necessary using phenylephrine (an {alpha}-receptor agonist) or phentolamine (an {alpha}-blocker). Alpha-stat acid–base management was employed throughout CPB. Aprotinin was not used.

2.3 Coronary artery grafts
These were performed according to the randomisation procedure. (a) ICCF group and (b) GR79236X group (Fig. 1): patients allocated to receive vehicle (0.9% sodium chloride) placebo (a) or GR79236X (b) were given the appropriate compound via a central venous line. Drug and placebo were supplied in numbered packs containing two identical 5 ml ampoules. The code for the numbers was held by the hospital Pharmacy until the study was completed. GR79236X was supplied at a concentration of 100 µg/ml. The volume of drug or placebo required to give 10 µg/kg (maximum dose 1 mg) was calculated from the patient's body weight and diluted in 100 ml of 0.9% sodium chloride. This was then administered via the central venous cannula as an infusion over a 10-min period at least 10 min prior to establishing CPB. The first distal anastomosis was performed at normothermia (36–37°C) during a fixed 10-min cross-clamp period as previously described [1,2]. The remaining coronary grafts were then performed using the standard cross-clamp fibrillation technique. (c) IPC group (Fig. 2): after establishing CPB, with the core temperature at 36–37°C, patients received two 3-min periods of aortic cross-clamping with rapid epicardial pacing (90 beats/min), each followed by 2 min of reperfusion (unpaced) before the first graft was performed. The coronary artery grafts were performed as in groups (a) and (b) above.


Figure 1
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Protocol for intermittent cross-clamp fibrillation (ICCF) and GR79236X. Drug or placebo is infused over a 10-min period at least 10 min prior to commencing cardiopulmonary bypass (CPB). Once CPB is established, the patient is warmed to 37°C for the first coronary artery graft, which is performed over a fixed 10-min period, then cooled to 32°C for the remaining grafts. All grafts are performed using the intermittent cross-clamp fibrillation technique.

 

Figure 2
View larger version (6K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Ischemic preconditioning (IPC) protocol. The patient is first warmed to 37°C on cardiopulmonary bypass. IPC is induced by two 3-min periods of aortic cross-clamping, each followed by 2 min of reperfusion. The grafts are performed using the intermittent cross-clamp fibrillation technique. The first coronary artery graft is performed at 37°C with an obligatory 10-min cross-clamp time. The patient is cooled to 32°C for the remaining grafts.

 
2.4 Study end points
The primary endpoint of the study was release of troponin T. Secondary end points included ECG changes, post-operative arrhythmias and indicators of myocardial function including cardiac output measurements (transesophageal doppler), use of inotropic agents and time to extubation. Blood samples for troponin T assay were taken from each patient 1, 6, 24 and 72 h after surgery. The serum was extracted and stored at –20°C prior to analysis. The clinical bioanalysts were blinded to the treatment groups. Cardiac output was assessed using the transesophageal doppler (ODM II, Abbott) and recorded following induction of anaesthesia, before CPB, 10 min after terminating CPB, on arrival in the cardiac recovery unit, and 2, 4 and 6 h following termination of CPB. Heart rate and blood pressure were recorded at the same time, as were the use of inotropic agents or the intra-aortic balloon pump. Post-operative 12-lead ECGs were recorded immediately and 1, 3 and 5 days after surgery, and any changes documented. Particular attention was given to new Q wave appearance, T wave changes and arrhythmias. Post-operative complications and adverse events were documented.

2.5 Statistics
Our previous studies predicted a difference in serum troponin T of approximately 1 µg/l between preconditioned and non-preconditioned hearts [2]. For this study to have over 90% power to detect a difference of at least 0.5 µg/l in serum troponin T release between groups, we determined that we would require 10 patients in each treatment group. This assumes a standard deviation of 0.2 µg/l with significance declared at the two-sided 5% level. Results were analysed using one-way ANOVA with Fisher's post-hoc test for continuous data, and the {chi}2 or Fisher's exact test for categorical data.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Patient demographics and operation details (Table 1)
The groups were well matched for age and sex, for height and weight, and for Parsonnet Risk Score [17]. An average of 3.2 grafts was performed per patient in each group. There was no significant difference in CPB times between the ICCF and GR79236X groups. CPB time was significantly prolonged in the IPC group. There was no significant difference between the groups in aortic cross-clamp (ischemic) times for grafting. GR79236X administration had no significant haemodynamic effect (data not shown).


View this table:
[in this window]
[in a new window]

  		Table 1 Patient demographics and operation times (min)

 
3.2 Clinical outcomes (Table 2)
There were no adverse events related to the treatments (IPC and GR79236X) under investigation and no deaths in this study. None of the patients developed new Q wave infarcts. Post-operative ECG changes (T wave inversion) were noted in 17%, with no significant difference between groups (Fisher's exact test, P=0.5). Atrial fibrillation occurred in 33% of patients, again with no significant difference between groups. There was no incidence of ventricular dysrhythmia. With regard to post-operative myocardial function or inotrope requirement, time to extubation and post-operative complications, there were no significant differences between groups.


View this table:
[in this window]
[in a new window]

  		Table 2 Clinical outcomes

 
3.3 Troponin T release
In all groups, troponin T release was detectable following CPB, rising to a plateau at 72 h (Fig. 3). Mean troponin T release, 72 h post surgery, was significantly reduced in the IPC group (0.58 µg/l; P=0.04, ANOVA) compared with control (ICCF, 1.32 µg/l) but not in the GR79236X group (1.22 µg/l; P=0.85, ANOVA).


Figure 3
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Release profile of cardiac troponin T following CABG surgery. Mean cardiac troponin T (TnT) release at 1, 6, 24 and 72 h following cardiopulmonary bypass, with standard error bars. There is an initial sharp rise in serum TnT, which reflects reversible myocyte injury. TnT levels plateau after 48 h, reflecting release as a result of ongoing myocyte necrosis (*P=0.04; one-way ANOVA).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study shows that ischemic preconditioning appears to confer additional myocardial protection beyond that provided by the intermittent cross-clamp fibrillation technique alone, as manifested by a reduction in cardiac troponin T release. Cardiac troponin T, a regulatory protein in the contractile apparatus, is well recognised as a sensitive marker of myocardial injury [18]. Its release profile following myocardial ischemia and reperfusion has been well-characterised [19]. Troponin T release following CABG has been noted to increase with number of grafts performed, detectable both intra-operatively in coronary sinus blood and post-operatively. Plateau levels exceeding 3.4 µg/l 48 h post-operatively correlate well with peri-operative myocardial infarction (as evidenced by new Q wave on ECG and creatine kinase-MB levels) [20]. Although mean troponin T levels in all groups in this study are well below this threshold level for clinically detectable myocardial infarction, the persistence of troponin T release up to 72 h following surgery does indicate some subclinical myocyte necrosis. The biological significance of this is unknown and remains to be ascertained. However, our results support the improved myocardial protection that ischemic preconditioning confers, as previously demonstrated by us in this setting [1,2]. In contrast, pretreatment with the specific adenosine A1 receptor agonist GR79236X does not appear to have affected (either beneficially or adversely) myocardial protection.

There is a large body of evidence from both animal and in vitro human tissue models [6–9] that adenosine A1 receptor activation prior to the onset of ischemia is protective, the mechanism of protection mimicking that of ischemic preconditioning. GR79236X has shown similar protective effects in animal models using a dose of 3.5 µg/kg [15,16]. Administration of GR79236X is associated with a reduction in plasma levels of non-esterified fatty acids, an action indicative of adenosine A1 receptor activation [21,22]. Maximal lowering of non-esterified fatty acids during pre-clinical testing in healthy volunteers was evident at a dose of 10 µg/kg (unpublished data provided by Glaxo Wellcome), the dose used in this study. In order to achieve this dose without the potential diluting effect of the cardiopulmonary bypass circuit (which was routinely primed with Hartmann's solution (1.5 l) and Gelofusine (500 ml)), the drug was administered prior to commencing cardiopulmonary bypass. A 10-min interval, before cardiopulmonary bypass was initiated, was considered sufficient for the drug to take effect and activate the preconditioning signaling pathway prior to ischemia. In contrast, ischemic preconditioning was administered only after cardiopulmonary bypass was commenced as this provided circulatory support while the ascending aorta was cross-clamped. This resulted in prolonged CPB times in this group, yet in spite of this the myocardial protection seen was superior and clinical outcomes were not affected. We do not believe that the difference in timing between the two ‘preconditioning’ stimuli would have contributed to any difference in protection seen. The protective effects of classical ischemic preconditioning have been shown to persist for up to 1 h, attenuation of protection occurring only when the time interval between the preconditioning stimulus and the longer ischemic insult exceeds an hour [23].

Our finding that the selective adenosine A1 agonist GR79236X did not show a protective benefit in CABG patients does not detract from the existing evidence supporting the role of adenosine and its receptors in the cardioprotection conferred by ischemic preconditioning. The failure to demonstrate any significant cardioprotective benefit with GR79236X in this study may be due to a number of factors. Previous research has shown that a certain threshold of stimulation has to be reached in order to elicit the preconditioning response, which appears to be an ‘all-or-nothing’ phenomenon [24,25]. Also, the duration of ischemia required to elicit classical preconditioning is known to vary between species [26]. Thus, the dose of GR79236X used may have been insufficient to reach the threshold to stimulate the myocardial preconditioning signaling pathway in man, compared with the endogenous levels of mediators (including adenosine, bradykinin [24], endothelin [27] and opioids [28]) that are released following an ischemic (preconditioning) stimulus. Another possible conclusion is that stimulation of the adenosine A1 receptor alone is inadequate to precondition the human heart in this setting. Stimulation of both A1 and A3 adenosine receptors [9,29] may be required to precondition the human heart in vivo. Finally, many drugs used during cardiac surgery have been noted to have preconditioning properties in the laboratory setting. We have tried to minimise any possible confounding factor by either removing them from the study protocol (isoflurane [30]) or standardising patient exposure (opioids [28], specifically morphine premedication and fentanyl in the early stages of the operation when the chest is opened). Any benefit that the control group may have gained from opioid exposure was not sufficient to mask the beneficial effects of ischemic preconditioning. Whether or not this could have biased the results with respect to GR79236X is purely speculative.

In this study we have used intermittent cross-clamp fibrillation as the control method of myocardial protection. This is a well-established, though somewhat misunderstood, technique which remains popular in the UK. It has been suggested by some, including ourselves in an earlier report [1], that this technique invokes myocardial preconditioning as a mechanism of protection. In view of our previous [1,2] and current studies that show additional protection conferred by a formal ischemic preconditioning protocol, we no longer believe this to be the case, given the ‘all-or-nothing’ nature of preconditioning protection. We acknowledge that cardioplegia in its many forms is internationally more popular for myocardial protection in cardiac surgery. To date, however, there are no studies that demonstrate any difference in myocardial protection between intermittent cross-clamp fibrillation and cardioplegia [31,32]. Furthermore, the clinical advantages of blood cardioplegia over crystalloid cardioplegia appear to be at best marginal [33] and may not be present at all [34,35]. There have been few clinical studies examining preconditioning in comparison with cardioplegia for myocardial protection. Those studies that have been done have yielded conflicting results, largely attributable to the different cardioplegic strategies, preconditioning protocols and end points used [36–39]. The use of adenosine-supplemented cardioplegia solutions (where adenosine is administered at the onset of ischemia as part of the cardioplegic solution) is quite different from pharmacological preconditioning, working by as yet unknown mechanisms [40,41]. Therefore, in our attempt to identify and validate an agent that may have pharmacological preconditioning properties, we chose to use our established protocols of intermittent cross-clamp fibrillation and ischemic preconditioning [1,2] as negative and positive controls, respectively, in this study.

This was a small clinical study in a highly selected patient population. With these relatively small numbers and a low-risk patient population, significant differences in clinical outcome were not expected and did not occur. Indeed, this study was not powered to detect differences in clinical outcome. This contrasts with a similar study carried out in patients with poor left ventricular function (ejection fraction<30%), in which adenosine (250–350 µg/kg) infusion prior to commencing CPB resulted in improved hemodynamic function as well as reducing post-operative creatine kinase release [42]. Clinical studies of preconditioning are few and far between. Those carried out in the setting of coronary angioplasty are limited by the small amount of myocardial ischemia sustained during balloon inflation. CABG surgery is an ideal setting to examine the efficacy of myocardial protection, a measurable release of cardiac troponin T occurring regardless of cardioprotective strategy. The study we present here is unique in attempting to explore the possibility of pharmacological preconditioning of the myocardium with a novel selective adenosine A1 receptor agonist in a clinical setting. Although we have not achieved a positive result, we have at least reaffirmed the benefits of ischemic preconditioning even in low-risk patients and established that selective adenosine A1 receptor activation alone appears to be insufficient to precondition the human heart under the conditions studied. The challenge remains, to confirm the protective benefits of ischemic preconditioning in a wider patient population and to identify and examine other possible methods of pharmacological preconditioning that could be clinically relevant.

Time for primary review 27 days.


   Acknowledgements
 
We thank the British Heart Foundation for their continued support, the Pharmacy and theatre staff at the Middlesex Hospital for their assistance and patience throughout this study, and the Biochemistry Department at the Royal Brompton Hospital for performing the troponin T assays.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Yellon D.M., Alkhulaifi A.M., Pugsley W.B. Preconditioning the human myocardium. Lancet (1993) 342:276–277.[CrossRef][Web of Science][Medline]
  2. Jenkins D.P., Pugsley W.B., Alkhulaifi A.M., et al. Ischemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart (1997) 77(4):314–318.[Abstract/Free Full Text]
  3. Downey J.M., Liu G.S., Thornton J.A. Adenosine and the anti-infarct effects of preconditioning. Cardiovasc. Res. (1993) 27(1):3–8.[Free Full Text]
  4. Mullane K., Bullough D. Harnessing an endogenous cardioprotective mechanism: cellular sources and sites of action of adenosine. J. Mol. Cell. Cardiol. (1995) 27(4):1041–1054.[CrossRef][Web of Science][Medline]
  5. Liu G., Thornton J., Van Winkle D., et al. Protection against infarction afforded by preconditioning is mediated by A1 receptors in rabbit heart. Circulation (1991) 84(1):350–356.[Abstract/Free Full Text]
  6. Tsuchida A., Liu G.S., Wilborn W.H., Downey J.M. Pretreatment with the adenosine A1 selective agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), causes a sustained limitation of infarct size in rabbits. Cardiovasc. Res. (1993) 27:652–656.[Web of Science][Medline]
  7. Dana A., Jonassen A.K., Yamashita N., Yellon D.M. Adenosine A(1) receptor activation induces delayed preconditioning in rats mediated by manganese superoxide dismutase. Circulation (2000) 101(24):2841–2848.[Abstract/Free Full Text]
  8. Bell R.M., Rees D.D., Yellon D.M. The protection observed during delayed preconditioning in the heart appears independently of iNOS: a study in iNOS knockout mice. Circulation (Abstract) (1999) 100(18 Suppl. I):I-242.
  9. Carr C.S., Hill R.J., Masamune H., et al. Evidence for a role for both the adenosine A1 and A3 receptors in protection of isolated human atrial muscle against simulated ischaemia. Cardiovasc. Res. (1997) 36(1):52–59.[Abstract/Free Full Text]
  10. Parratt J.R., Kane K.A. KATP channels in ischemic preconditioning. Cardiovasc. Res. (1994) 28:783–787.[Free Full Text]
  11. Downey J.M., Cohen M.V. Signal transduction in ischemic preconditioning. Adv. Exp. Med. Biol (1997) 430:39–55.[Web of Science][Medline]
  12. Kouchi I., Murakami T., Nawada R., Akao M., Sasayama S. KATP channels are common mediators of ischemic and calcium preconditioning in rabbits. Am. J. Physiol. (1998) 274(4 pt 2):H1106–1112.[Web of Science][Medline]
  13. Carr C.S., Grover G.J., Pugsley W.B., Yellon D.M. Comparison of the protective effects of a highly selective ATP-sensitive potassium channel opener and ischemic preconditioning in isolated human atrial muscle. Cardiovasc. Drugs Ther. (1997) 11(3):473–478.[CrossRef][Web of Science][Medline]
  14. Gurden M.F., Coates J., Ellis F., et al. Functional characterisation of three adenosine receptor types. Br. J. Pharmacol. (1993) 109(3):693–698.[Web of Science][Medline]
  15. Travers A., Middlemeiss D., Louttit J.B. Cardioprotection after repeated dosing with GR79236, an adenosine A1 receptor agonist. Br. J. Pharmacol. (Abstract) (1998) 124(Proc. Suppl.):102P.
  16. Louttit J.B., Hunt A.A., Maxwell M.P., Drew G.M. The time course of cardioprotection induced by GR79236, a selective adenosine A1-receptor agonist, in myocardial ischaemia-reperfusion injury in the pig. J. Cardiovasc. Pharmacol. (1999) 33:285–291.[CrossRef][Web of Science][Medline]
  17. Parsonnet V., Dean D., Bernstein A.D. A method of uniform stratification of risk for evaluating the results of surgery in acquired heart disease. Circulation (1989) 79(Suppl. I):3–12.[Web of Science]
  18. Katus H.A., Schoeppenthau M., Tanzeem A., et al. Non-invasive assessment of perioperative myocardial cell damage by circulating cardiac troponin T. Br. Heart J. (1991) 65:259–264.[Abstract/Free Full Text]
  19. Katus H.A., Remppis A., Scheffold T., Diederich K.W., Kuebler W. Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am. J. Cardiol. (1991) 67:1360–1367.[CrossRef][Web of Science][Medline]
  20. Carrier M., Pellerin M., Perrault L.P., Solymoss B.C., Pelletier L.C. Troponin levels in patients with myocardial infarction after coronary artery bypass grafting. Ann. Thorac. Surg. (2000) 69:435–440.[Abstract/Free Full Text]
  21. Strong P., Anderson R., Coates J., et al. Suppression of non-esterified fatty acids and triacylglycerol in experimental animals by the adenosine analogue GR79236. Clin. Sci. (1993) 84(6):663–669.[Web of Science][Medline]
  22. Merkel L.A., Hawkins E.D., Colussi D.J., et al. Cardiovascular and antilipolytic effects of the adenosine agonist GR79236. Pharmacology (1995) 51(4):224–236.[Web of Science][Medline]
  23. Jenkins D.P., Baxter G.F., Yellon D.M. The pathophysiology of ischaemic preconditioning. Pharmacol. Res. (1995) 31:219–224.[Web of Science][Medline]
  24. Goto M., Liu Y., Yang X.M., et al. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ. Res. (1995) 77:611–621.[Abstract/Free Full Text]
  25. Morris S.D., Yellon D.M. Angiotensin-converting enzyme inhibitors potentiate preconditioning through bradykinin B2 receptor activation in human heart. J. Am. Coll. Cardiol. (1997) 29:1599–1606.[Abstract]
  26. Lawson C.S., Downey J.M. Preconditioning: state of the art myocardial protection. Cardiovasc. Res. (1993) 27:542–550.[Free Full Text]
  27. Vegh A., Szekeres L., Parratt J. Preconditioning of the ischemic myocardium; involvement of the L-arginine nitric-oxide pathway. Br. J. Pharmacol. (1992) 107:648–652.[Web of Science][Medline]
  28. Schultz J.E.J., Rose E., Yao Z., Gross G.J. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am. J. Physiol. (1995) 268:H2157–H2161.[Web of Science][Medline]
  29. Liu G.S., Richards S.C., Olsson R.A., et al. Evidence that the adenosine A3 receptor may mediate the protection afforded by preconditioning in the isolated rabbit heart. Cardiovasc. Res. (1994) 28(7):1057–1061.[Abstract/Free Full Text]
  30. Ismaeil M.S., Tkachenko I., Gamperl A.K., Hickey R.F., Cason B.A. Mechanisms of isoflurane-induced myocardial preconditioning in rabbits. Anesthesiology (1999) 90(3):812–821.[CrossRef][Web of Science][Medline]
  31. Pepper J.R., Lockey E., Cankovic-Darracott S., Braimbridge M.V. Cardioplegia versus intermittent ischemic arrest in coronary bypass surgery. Thorax (1982) 37:887–892.[Abstract/Free Full Text]
  32. Anderson J.R., Hossein-Nia M., Kallis P., et al. Comparison of two strategies for myocardial management during coronary artery operations. Ann. Thorac. Surg. (1994) 58(3):768–772.[Abstract]
  33. Jacquet L.M., Noirhomme P.H., Van Dyck M.J., et al. Randomised trial of intermittent antegrade warm blood versus cold crystalloid cardioplegia. Ann. Thorac. Surg. (1999) 67(2):471–477.[Abstract/Free Full Text]
  34. Shanewise J.S., Kosinski A.S., Coto J.A., Jones E.L. Prospective randomised trial comparing blood and oxygenated crystalloid cardioplegia in reoperative coronary artery bypass grafting. J. Thorac. Cardiovasc. Surg. (1998) 115(5):1166–1171.[Abstract/Free Full Text]
  35. Hendrikx M., Jiang H., Gutermann H., et al. Release of cardiac troponin I in antegrade crystalloid versus blood cardioplegia. J. Thorac. Cardiovasc. Surg. (1999) 118(3):452–459.[Abstract/Free Full Text]
  36. Perrault L.P., Menasche P., Bel A., et al. Ischemic preconditioning in cardiac surgery: a word of caution. J. Thorac. Cardiovasc. Surg. (1996) 112:1378–1386.[Abstract/Free Full Text]
  37. Kaukoranta P.K., Lepojarvi M.P., Ylitalo K.V., Kiviluoma K.T., Peuhkurinen K.J. Normothermic retrograde blood cardioplegia with or without preceding ischemic preconditioning. Ann. Thorac. Surg. (1997) 63:1268–1274.[Abstract/Free Full Text]
  38. Illes R.W., Swoyer K.D. Prospective, randomised clinical study of ischemic preconditioning as an adjunct to intermittent cold blood cardioplegia. Ann. Thorac. Surg. (1998) 65:748–753.[Abstract/Free Full Text]
  39. Li G., Chen S., Lu E., Li Y. Ischemic preconditioning improves preservation with cold blood cardioplegia in valve replacement patients. Eur. J. Cardiothorac. Surg. (1999) 15:653–657.[Abstract/Free Full Text]
  40. de Jong J.W., van der Meer P., van Loon H., Owen P., Opie L.H. Adenosine as an adjunct to potassium cardioplegia: effect on function, energy metabolism, and electrophysiology. J. Thorac. Cardiovasc. Surg. (1990) 100:445–454.[Abstract]
  41. Vinten-Johansen J., Thourani V.H., Ronson R.S., et al. Broad-spectrum cardioprotection with adenosine. Ann. Thorac. Surg. (1999) 68:1942–1948.[Abstract/Free Full Text]
  42. Lee H.T., LaFaro R.J., Reed G.E. Pretreatment of human myocardium with adenosine during open heart surgery. J. Card. Surg. (1995) 10:665–676.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur. J. Cardiothorac. Surg.Home page
V. Venugopal, A. Ludman, D. M. Yellon, and D. J. Hausenloy
'Conditioning' the heart during surgery
Eur. J. Cardiothorac. Surg., June 1, 2009; 35(6): 977 - 987.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. N. Peart and J. P. Headrick
Clinical cardioprotection and the value of conditioning responses
Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1705 - H1720.
[Abstract] [Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
S. R. Walsh, T. Y. Tang, P. Kullar, D. P. Jenkins, D. P. Dutka, and M. E. Gaunt
Ischaemic preconditioning during cardiac surgery: systematic review and meta-analysis of perioperative outcomes in randomised clinical trials
Eur. J. Cardiothorac. Surg., November 1, 2008; 34(5): 985 - 994.
[Abstract] [Full Text] [PDF]

Home page
 Card Surg AdultHome page
R. M. Mentzer Jr, M. S. Jahania, and R. D. Lasley
Myocardial Protection
Card. Surg. Adult, January 1, 2008; 3(2008): 443 - 464.
[Full Text]

Home page
 Br J AnaesthHome page
J. R. Sneyd, J. A. Langton, L. G. Allan, J. E. Peacock, and D. J. Rowbotham
Multicentre evaluation of the adenosine agonist GR79236X in patients with dental pain after third molar extraction
Br. J. Anaesth., May 1, 2007; 98(5): 672 - 676.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. M.H. Cheung, R. K. Kharbanda, I. E. Konstantinov, M. Shimizu, H. Frndova, J. Li, H. M. Holtby, P. N. Cox, J. F. Smallhorn, G. S. Van Arsdell, et al.
Randomized Controlled Trial of the Effects of Remote Ischemic Preconditioning on Children Undergoing Cardiac Surgery: First Clinical Application in Humans
J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2277 - 2282.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
D. Ramzy, V. Rao, and R. D. Weisel
Clinical applicability of preconditioning and postconditioning: The cardiothoracic surgeons's view
Cardiovasc Res, May 1, 2006; 70(2): 174 - 180.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
R. A. Kloner and S. H. Rezkalla
Preconditioning, postconditioning and their application to clinical cardiology
Cardiovasc Res, May 1, 2006; 70(2): 297 - 307.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
G. A. Rongen, W. J.G. Oyen, B. P. Ramakers, N. P. Riksen, O. C. Boerman, N. Steinmetz, and P. Smits
Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans
Circulation, January 18, 2005; 111(2): 173 - 178.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
D. M. YELLON and J. M. DOWNEY
Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology
Physiol Rev, October 1, 2003; 83(4): 1113 - 1151.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
J. Vaage and G. Valen
Preconditioning and cardiac surgery
Ann. Thorac. Surg., February 1, 2003; 75(2): S709 - 714.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
T. L. Vanden Hoek, Y. Qin, K. Wojcik, C.-Q. Li, Z.-H. Shao, T. Anderson, L. B. Becker, and K. J. Hamann
Reperfusion, not simulated ischemia, initiates intrinsic apoptosis injury in chick cardiomyocytes
Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H141 - H150.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
U. Sunderdiek, S. Schmitz-Spanke, B. Korbmacher, E. Gams, and J. D. Schipke
Preconditioning: myocardial function and energetics during coronary hypoperfusion and reperfusion
Ann. Thorac. Surg., December 1, 2002; 74(6): 2147 - 2155.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Teoh, L.K.K.
Right arrow Articles by Yellon, D.M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Teoh, L.K.K.
Right arrow Articles by Yellon, D.M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?