Cyclosporine A reduces infarct size and has no

Cyclosporine A reduces infarct size and has no detrimental effect of LV remodeling in STEMI patients Michel Ovize Cardiology Hospital and Inserm U 886 Lyon University, France

Previous work by Piot et al. (NEJM 2008) Objective: determine whether cyclosporine A can reduce infarct size in STEMI patients Cyclosporine A (or saline) (2. 5 mg/kg, IV bolus) t-10 min STEMI < 12 hrs PCI treatment LAD TIMI flow grade 0 -1 No visible collaterals t 0 Day 1 -3 CK / Tn. I release Infarct size Direct stenting Coronary artery occlusion Reperfusion Day 5 MRI

Reduction of cardiac enzymes release by cyclosporine A Piot et al. NEJM 2008 6000 250 CK release Control 200 Cs. A 4000 150 3000 100 2000 50 1000 0 CK release 1. 2. 105 control Cs. A 1. 0. 105 0. 8. 105 0. 6. 105 0. 4. 105 0. 2. 105 0 10 30 50 ACS (%) 70 0 0 20 40 60 72 h 66 h 60 h 54 h 48 h 42 h 36 h 30 h 24 h 20 h h h 16 8 h 12 Tn. I release 1. 2. 105 AUC (arbitrary units) 1. 4. 105 4 h . h h h 72 66 60 h 54 h 48 24 h 30 h 36 h 42 h h 20 16 12 A dm 8 h . 4 h 0 A dm (UI/L) 5000 AUC (arbitrary units) Tn. I release Control Cs. A

MRI infarct size (day 5) area of hyperenhancement (g) 120 70 60 50 * 40 30 20 10 0 Piot et al. NEJM 2008; 359: 473 -81 control cyclosporine

Mewton et al. J Am Coll Cardiol 2010; 55: 1200– 5

Rationale • Cs. A can reduce infarct size in STEMI patients. It is therefore expected that this protective effect may be associated with a reduced adverse LV remodeling • However, experimental evidence indicates that Cs. A, via anti-hypertrophic mechanisms, may favor an adverse remodeling response of the LV after STEMI • We then assessed LV volumes and wall thickness by MRI at 5 days and 6 months after AMI in a population of patients that had received Cs. A as an adjunct to PCI revascularization

Follow up CMR at 6 months post-MI Cyclosporine A or saline t-10 min t 0 Day 5 MRI 6 Month MRI PCI Coronary artery occlusion Mewton et al. JACC 2010 Reperfusion

infarct size at 6 months (grams) 60 50 * 40 30 20 10 0 Control Cyclosporine

Cyclosporine in acute myocardial infarction Mewton et al. (JACC 2010)

Follow up CMR at 6 months post-MI Cyclosporine A t-10 min t 0 Day 5 MRI 6 Month MRI PCI Coronary artery occlusion Mewton et al. J Am Coll Cardiol 2010; 55: 1200– 5 Reperfusion

200 LV EDV (ml) 160 120 Cs. A 80 control 40 0 10 20 30 40 MRI Infarct Size (g) 50 60 There was a significant correlation between left ventricular end-diastolic volume (LVEDV) and infarct size at 6 months (r 2=0. 40; p<0. 05) in the whole group of patients

140 120 LV ESV (ml) 100 80 60 40 20 Cs. A control 0 0 10 20 30 40 MRI Infarct Size (g) 50 60 There was a significant correlation between left ventricular end-systolic volume (LVESV) and infarct size at 6 months (r 2=0. 66; p<0. 05) in the whole group of patients

70 control Cs. A LV EF (%) 60 50 40 30 20 0 10 20 30 40 MRI_Infarct Size (g) 50 60 There was a significant correlation between left ventricular ejection fraction (LVEF) and infarct size at 6 months (r 2=0. 72; p<0. 05) in both groups of patients

MRI at 6 months after cyclosporine-treated MI 60 control MRI_IS (g) at M 6 50 40 * Cs. A 30 20 10 0 Mewton et al. (JACC 2010) *

Conclusion • Cyclosporine used at the moment of acute myocardial infarction reperfusion reduces infarct size and does not have a detrimental effect of LV remodeling. • These results obtained from a limited population of patients must be confirmed by large-scale trials

Michel OVIZE, MD, Ph. D