PRE-CLINICAL RESEARCH: EDITORIAL COMMENT
Lizard Spit and Reperfusion Injury*
Ian G. Webb, BMBCh, MRCP,
Rupert Williams, MB, BS and
Michael S. Marber, FRCP, FACC, PhD*
King's College London BHF Centre, Cardiovascular Division, The Rayne Institute, St. Thomas' Hospital, London, United Kingdom
* Reprint requests and correspondence: Dr. Michael S. Marber, Department of Cardiology, Kings College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, United Kingdom (Email: mike.marber{at}kcl.ac.uk).
Key Words: exenatide • glucagon-like peptide 1 • myocardial infarction • reperfusion
Although the incidence of ST-segment elevation myocardial infarction (STEMI) is declining in industrialized nations, there are still an estimated 500,000 events annually in the U.S. (1). Furthermore, the in-hospital mortality is 6% to 7%, and over 15% of survivors to discharge experience a recurrent cardiovascular event by 6 months (2). Infarct size is the key determinant of outcome, and prompt reperfusion of the occluded epicardial artery is imperative to reduce infarction volume and improve mortality and morbidity. Paradoxically, however, reperfusion seems to contribute to additional myocardial damage over and above that caused by the original ischemic insult. This additional damage is known as reperfusion injury and if it could be prevented an already exemplary treatment would be further improved.
The concept of reperfusion injury has been recognized and its existence debated for over 30 years (3). At the cellular level there are a variety of associated/causative pathophysiological processes, including oxidative stress, intracellular calcium dysregulation, inflammation, and rapid normalization of intracellular pH (4). Animal models suggest that reperfusion injury might contribute up to 50% of ultimate infarction volume (4), and therefore its prevention should improve outcome. Unfortunately, despite numerous interventions showing promise in preclinical studies, very few have proved effective in clinical trials, and none has yet impacted on routine clinical practice (4,5).
In this issue of the Journal, Timmers et al. (6) present data in which the incretin mimetic exenatide significantly reduces myocardial infarction and improves left ventricular (LV) contraction and relaxation when it is given at reperfusion. These findings gain clinical relevance and immediacy through the use of an approved drug, a large animal model, and the assessment of infarction after a long duration of reperfusion.
Exenatide (sold commercially as "Byetta," Amylin-Lilly, San Diego, California) is currently licensed for parenteral use as an adjunctive therapy in patients with poorly controlled type II diabetes. Exenatide is a synthetic analogue of exendin-4, also known as "lizard spit" and found in the salivary secretions of the Gila monster, Heloderma suspectum (7). This 39-residue reptilian peptide is pharmacologically similar to mammalian glucagon-like peptide (GLP)-1 with which it shares 53% of its primary amino acid sequence (7,8). The GLP-1 is a gut-derived incretin hormone that is secreted by the intestine in response to nutrients. Like GLP-1, exenatide's glucoregulatory effects are mediated through a number of different mechanisms, including augmentation of glucose-stimulated insulin secretion (hence with low risk of a hypoglycemic overshoot), suppression of postprandial glucagon secretion, delayed gastric emptying, and hypothalamic-mediated satiety of appetite (9). These actions are thought to be mediated via the GLP-1 receptor present in the gastrointestinal tract, pancreas, lung, kidney, brain, and heart (10).
Importantly, exenatide lacks the alanine residue found at position 2 of GLP-1 that directs its degradation. Consequently, exenatide has a very much longer plasma half-life than GLP-1 (approximately 2.4 h vs. 1 to 4 min). The alanine-directed endopeptidase predominantly responsible for the breakdown of GLP-1 is dipeptidyl peptidase (DPP)-IV. Thus, orally available inhibitors of DPP-IV increase the half-life of GLP-1 and are licensed similarly to exenatide for the treatment of type II diabetes.
Exenatide/exendin-4 and GLP-1 are known to have a number of cardiovascular effects. In isolated perfused rat hearts exendin-4 reduced infarct size when administered at reperfusion (11). This effect was abrogated by co-administration of a GLP-1 receptor antagonist. However, the positive inotropic effect of exendin-4 was independent of the GLP-1 receptor (11). Such GLP-1 receptor-independent effects are expected, because exendin-4 is not a true reptilian homologue of GLP-1 (8).
Experiments in both isolated and in vivo rat hearts suggest that GLP-1 significantly attenuates reperfusion injury and reduces infarct size by approximately 50% when coadministered with a DPP-IV inhibitor (12). The GLP-1 seems equally protective when given before lethal ischemia as a preconditioning agent (13). In a model of sub-lethal ischemic injury, a 24-h intravenous infusion of GLP-1 after a 10-min circumflex coronary artery occlusion in the dog diminished stunning independent of alterations in systemic hemodynamic status and contractile function in the remote myocardium (14).
The GLP-1 also exerts important effects on the failing heart; a 48-h infusion of GLP-1 in a canine-model of pacing-induced cardiomyopathy resulted in enhanced myocardial insulin sensitivity and contractility (15). More recently, chronic subcutaneous GLP-1 over 3 months in a rat model of hypertension-related heart failure improved myocardial glucose uptake and reduced myocyte apoptosis, contractile dysfunction, and group mortality from 66% to 28% (16).
These observations have begun to be translated into small, nonrandomized, pilot clinical studies. A 5-week continuous subcutaneous GLP-1 infusion in 12 patients with ejection fractions <40% and New York Heart Association functional class III to IV symptoms was associated with significant improvements in objective measures of LV function and symptoms in both diabetic and nondiabetic patients (17). A 48-h perioperative infusion of GLP-1 in patients with preserved LV function undergoing elective bypass surgery significantly reduced inotrope requirements and improved glycemic control in the immediate postoperative period (18). An open, nonrandomized, pilot study has even examined the role of GLP-1 in patients with STEMI reperfused by primary percutaneous coronary intervention. Eleven such patients with impaired LV systolic function (LVEF <40%) received a 72-h GLP-1 infusion starting on average 212 min after the onset of reperfusion (19). Despite this delay, the limited number of observations and an echocardiographic end point, GLP-1 significantly improved recovery of LVEF and regional/global wall motion compared with the 10 control subjects (19).
The data from Timmers et al. in this issue of the Journal (6) add further support to the cardioprotective effects of incretin analogues in a clinically applicable model of ischemia-reperfusion. The observed reduction in infarction (32.7% vs. 53.6%, p = 0.03) with exenatide is impressive and accompanied by improvements in systolic and diastolic function as measured by echocardiography and invasive simultaneous measurement of LV pressure and volume. These end points were collected after 3 days of reperfusion, effectively excluding a false-positive finding resulting from the delay rather than the prevention of reperfusion injury, although it could be argued that the results are predictable on the basis of the findings with GLP-1 summarized in the preceding text. As already mentioned exenatide is not a true GLP-1 homologue (8). Furthermore, unlike GLP-1, its half-life allowed administration twice daily rather than by continuous infusion.
The authors are to be congratulated on a well-designed and highly translational study; however, mechanistic insight is still limited. Exenatide resulted in a significant increase in phosphorylated (active) Akt at 2 h, a reduction in pro-apoptotic caspase-3 at 4 h, and higher levels of anti-apoptotic Bcl-2 and reduced oxidative stress at 72 h of reperfusion. However, it is not clear whether any of these effects are causally related to protection. Furthermore, it is not clear whether it is the exenatide itself and/or the consequent increase in serum insulin that initiate protection. In the end such nuances become less important when the model and the intervention are so clinically pertinent.
It is likely that we, as cardiologists, will become more familiar with exenatide and the DPP-IV inhibitors as the tsunami of type II diabetes washes over our practice. On the basis of the study of Timmers et al. (6), it is possible that we might have the beginning of a flood defense. There is appreciable circumstantial evidence that the incretins and their mimetics will reduce cardiovascular risk as well as improve outcomes in those with a cardiovascular event. However, in the competition to find interventions that reduce reperfusion injury in the clinic, there is only 1 measure that matters: hard clinical end points.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction) J Am Coll Cardiol 2004;44:E1-E211.[CrossRef][Medline]2. Jneid H, Fonarow GC, Cannon CP, et al. Impact of time of presentation on the care and outcomes of acute myocardial infarction Circulation 2008;117:2502-2509.[Abstract/Free Full Text] 3. Follette D, Fey K, Livesay J, Maloney Jr. JV, Buckberg GD. Studies on myocardial reperfusion injury. I. Favorable modification by adjusting reperfusate pH. Surgery 1977;82:149-155.[Medline] 4. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury N Engl J Med 2007;357:1121-1135.[CrossRef][Web of Science][Medline] 5. Bolli R, Becker L, Gross G, Mentzer Jr. R, Balshaw D, Lathrop DA. Myocardial protection at a crossroads: the need for translation into clinical therapy Circ Res 2004;95:125-134.[Abstract/Free Full Text] 6. Timmers L, Henriques JPS, de Kleijn DPV, et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury J Am Coll Cardiol 2009;53:501-510.[Abstract/Free Full Text] 7. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402-7405.[Abstract/Free Full Text] 8. Pohl M, Wank SA. Molecular cloning of the helodermin and exendin-4 cDNAs in the lizard. Relationship to vasoactive intestinal polypeptide/pituitary adenylate cyclase activating polypeptide and glucagon-like peptide 1 and evidence against the existence of mammalian homologues. J Biol Chem 1998;273:9778-9784.[Abstract/Free Full Text] 9. Cvetkovic RS, Plosker GL. Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea) Drugs 2007;67:935-954.[CrossRef][Medline] 10. Holst JJ. The physiology of glucagon-like peptide 1 Physiol Rev 2007;87:1409-1439.[Abstract/Free Full Text] 11. Sonne DP, Engstrom T, Treiman M. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart Regul Pept 2008;146:243-249.[CrossRef][Web of Science][Medline] 12. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury Diabetes 2005;54:146-151.[Abstract/Free Full Text] 13. Bose AK, Mocanu MM, Carr RD, Yellon DM. Glucagon like peptide-1 is protective against myocardial ischemia/reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model Cardiovasc Drugs Ther 2005;19:9-11.[CrossRef][Web of Science][Medline] 14. Nikolaidis LA, Doverspike A, Hentosz T, et al. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines J Pharmacol Exp Ther 2005;312:303-308.[Abstract/Free Full Text] 15. Nikolaidis LA, Elahi D, Shen YT, Shannon RP. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy Am J Physiol Heart Circ Physiol 2005;289:H2401-H2408.[Abstract/Free Full Text] 16. Poornima I, Brown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP. Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure prone rat Circ Heart Fail 2008;1:153-160.[Abstract/Free Full Text] 17. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure J Card Fail 2006;12:694-699.[CrossRef][Web of Science][Medline] 18. Sokos GG, Bolukoglu H, German J, et al. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting Am J Cardiol 2007;100:824-829.[CrossRef][Web of Science][Medline] 19. Nikolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion Circulation 2004;109:962-965.[Abstract/Free Full Text]
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