1. Ischemic Conditioning and Endothelial Function Todd Anderson Libin Cardiovascular Institute University of Calgary

2. Disclosures Department of Cardiac Sciences and Libin Cardiovascular Institute – U of Calgary Grant support by Alberta Innovates –Merck, Amgen, Abbott

3. BASELINE (3.65 mm) REACTIVE HYPEREMIA (4.08 mm) Flow-Mediated Vasodilation FMD = 10.5 %

4. Microvasculature Philpott et al. ATVB 2007;27:2065

5. Flow-Mediated Vasodilation- Velocity Baseline Doppler (VTI=19.1cm) Hyperemic Doppler (VTI=60.5 cm) Co variance – 17%

6. Shear stress, hyperemic velocity and Risk Factors FATE – n=1477, Overall R 2 for hyperemic velocity = 0.171 *Unadjusted (univariate) Coefficient p value**Adjusted Coefficient Age-1.633<0.001-1.004 Systolic BP-0.894<0.001-0.489 Fasting Glucose-10.774<0.001-3.889 LDL-8.211<0.001-6.201 HDL21.187<0.00113.667 Current Smoking-2.8690.514---- CRP-1.712<0.001-0.915 BMI-3.898<0.001-1.930

7. Coronary Intervention and Endothelial Function * FMD is NO-dependent Joannides et al. Circ 95;91:1314 8 subjects A-mode Echo and RH

8. Adenosine probably plays a role at low perfusion pressures alone and in combination with K + ATP channels blockade Ischemia may shift control to small resistance vessels which are metabolically controlled (adenosine) May act through A receptors, inhibit NE release or via K + ATP channels blockade Important in debt repayment in reactive hyperemia Coronary Blood Flow - Metabolic Vasodilation Resistance Vessels - Adenosine

9. Ohara Y et al. Circulation 1995;92:898-903. Dietary Correction in previously cholesterol- fed rabbits normalizes superoxide radicals and improves endothelium- dependent dilation. Endothelial Function and Hypercholesterolemia

10. Endthelial Function and Risk Factors Brachial % FMD Celermajer et al. Lancet 92;340:1111

11. Ischemic Conditioning Ischemia-reperfusion injury –Kloner JCI 1974:54:1496 – No reflow in dogs –Reimer et al. Circulation 1977; 56:786 – wavefront of ischemic death –Braunwald and Kloner. JCI 1985;76:1713 – double edged sword and concept of stunned myocardium Circulation 1982 Ischemic conditioning –Murry et al. Circulation 1986; 74:1174 – IPC

12. Ischemic Conditioning Vinten-Johansen JAP 2007;103:1441 Significant parallelism between pre and post- conditioning

13. Ischemic Conditioning and Endothelial Function Ischemia-reperfusion injury causes injury and acute conduit and NO dependent micro-vessel endothelial dysfunction Pre and post-conditioning with IPC bouts of transient ischemia attenuate this abnormality Pharmacological conditioning prevents IR endothelial dysfunction acutely but less reliably chronically IPC improves LV function during acute myocardial infarction in some but not all studies Remote IPC also results in variable outcomes IPC may also have favorable effects on other outcomes including blood pressure

14. Ischemic Conditioning Kharbanda Circ 2001; 103:1624

15. Ischemic Conditioning Kharbanda Circ 2001; 103:1624 Attenuation of NO dependent increases in FBF post IR injury with activation of neutrophils as well Attenuation of FMD with pre-conditioning attenuating this abnormality

16. Remote Ischemic Conditioning Kharbanda Circ 2002; 106:2881 20 minutes of ischemia with and without 3 cycles of 5 minutes of IPC on the contra-lateral arm

17. Remote Ischemic Post-Conditioning Loukogeorgakis et al. Circulation 2007;116:1386 19 healthy subjects RIPC and RPostC 20 minutes of ischemia With and without glibenclamide to assess K+ ATP channels Both prevented the ↓ FMD with IR (PostC in leg but not arm) and this was blocked by glibenclamide

18. Ischemia-Reperfusion Injury Alhejily et al. Microcirculation 2013 45 normal subjects with 15 minutes of ischemia Attenuation of FMD but no change in hyperemic stimulus or PAT-index IR doesn’t impair microvascular function

19. Pharmacologic Conditioning - Statins Liuni et al. Clin Hemorheol 2010;45:161

20. Ischemic Conditioning Luca et al. JAHA 2013;2(1) 30 healthy subjects IR alone vs 1 day IPC vs 7 d IPC protocol 3 cycles of 5 min of ischemia and reperfusion Celecoxib did not change results. Both 1 and 7 days of IPC attenuated IR decrease in FMD

21. Ischemic Conditioning Luca et al. JAHA 2013;2(1) 30 healthy subjects IR alone vs 1 day IPC vs 7 d IPC protocol 3 cycles of 5 min of ischemia and reperfusion Celecoxib did not change results. Both 1 and 7 days of IPC attenuated IR decrease in FMD

22. Ischemic Post-Conditioning Staat et al. Circ 2005;112:2143 30 patients with primary PCI Randomized to 4 cycles of 1 min inflation/deflation prior to PCI AUC CK rise post MI

23. Ischemic Post-Conditioning Dwyer et al. J Interventional Cardiol; 2013;26:482. 102 patients with primary PCI Randomized to 4 cycles of 1 min inflation/deflation prior to PCI CMR EP of Area at Risk No change in EF or microvascular obstruction

24. Ischemic Conditioning Hausenloy Nature Reviews Cardiology 2011;8:619

25. Ischemic Conditioning and Endothelial Function Effect of acute or repeated episodes of IPC in patients with endothelial dysfunction is unknown Acute and 7 days of IPC can ameliorate the IR-induced decreases in FMD with no effect on measures of microvascular response (hyperemic velocity or PAT) Pre-conditioning may be more effective than post-conditioning in the forearm acute endothelial dysfunction model (and studies are mixed with AMI) Further studies are needed to assess the effects of longer term IPC on endothelial function and cardiovascular pathophysiology