Ischemic preconditioning

Ischemic preconditioning

The concept of ischemic preconditioning is that multiple short episodes of ischemia can protect the heart from a later sustained ischemia [1]. In an experimental study, 4 episodes of 5 minutes each, separated by 5 minutes of reperfusion followed by 40 minutes of occlusion showed 75% reduction in infarct size compared to controls. But this benefit was not there when the final occlusion time was 3 hours. Authors suggested that multiple pre-infarction anginal episodes may have a similar effect on limiting infarct size if myocardial infarction occurs subsequently. Others have suggested that similar mechanism might operate in warm-up phenomenon in angina [2]. Intermittent ischemia during aortic cross clamping in fibrillating heart during coronary artery bypass surgery is also a clinical model of ischemic preconditioning.

Ischemic preconditioning has also been studied during percutaneous coronary intervention. Clinical, ECG and coronary hemodynamic responses to sequential 90 second balloon occlusions of left anterior descending coronary artery were assessed in 12 patients [3]. Compared to the initial balloon occlusion, anginal discomfort was less in the second occlusion. Similarly, ST segment shift and mean pulmonary artery pressure was significantly lower in the second occlusion. Myocardial lactate production was also significantly lower during the second balloon occlusion.

It has been shown that ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, which is a selective ATP-sensitive potassium channel blocker [4]. In placebo treated patients in that study, severity of cardiac pain and the ST segment shift was lower after a second two minute balloon inflation. But in the glibenclamide treated patients, ST segment shift was similar to that during first inflation. The severity of cardiac pain was greater after the second inflation. This might explain the observation that patients receiving the earlier generation oral hypoglycemic agents for diabetes mellitus were at increased risk of cardiovascular mortality [5]. Those oral hypoglycemic agents were inhibitors of ATP-sensitive potassium (K_ATP) channel. Ischemic preconditioning is mediated by the activation of K_ATP channel.

AMISTAD-II trial showed that infarct size was reduced with 70 mcg/kg/min adenosine infusion and was correlated with fewer adverse clinical events. But the whole study did not show significant improvement of clinical outcomes in patients with ST elevation myocardial infarction undergoing reperfusion therapy along with adenosine infusion. The authors mentioned that a larger study with the 70 mcg/kg/min adenosine infusion is warranted [6]. Stimulation of adenosine receptors is known to simulate ischemic preconditioning.

Nicorandil is K_ATP channel opener. The significant clinical improvement in outcome due to a reduction in major coronary events noted in the IONA study of nicorandil in stable angina patients [7] could be explained by its effect on K_ATP channel which is similar to ischemic preconditioning. Using drugs to mimic ischemic preconditioning has been called pharmacological preconditioning.

Remote ischemic preconditioning can be done by inducing ischemia in another vascular territory. A multicenter randomized trial involving 1403 patients assessed the role of remote ischemic preconditioning prior to cardiac surgery [8]. Primary composite end point included death, myocardial infarction, stroke and acute renal failure up to the time of hospital discharge. Secondary end point was the occurrence of the components of primary end point within 90 days. Upper limb remote ischemic preconditioning done while patients were under propofol induced anaesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery.

References

1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986 Nov;74(5):1124-36.
2. Tomai F, Crea F, Chiariello L, Gioffrè PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation. 1999 Aug 3;100(5):559-63.
3. Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW Jr, Herrmann HC, Laskey WK. Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features. Circulation. 1990 Dec;82(6):2044-51.
4. Tomai F, Crea F, Gaspardone A, Versaci F, De Paulis R, Penta de Peppo A, Chiariello L, Gioffrè PA. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation. 1994 Aug;90(2):700-5. 
5. Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation. 1997 Jul 1;96(1):29-32. 
6. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW; AMISTAD-II Investigators. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol. 2005 Jun 7;45(11):1775-80.
7. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002 Apr 13;359(9314):1269-75. 
8. Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Böning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schön J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D, Zacharowski K; RIPHeart Study Collaborators. A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. N Engl J Med. 2015 Oct 8;373(15):1397-407.