Is Cyclosporine Immunosuppression Required to Effect Improved Myocardial Function Following Global Intracoronary Cardiosphere‐Derived Cells After Acute Myocardial Infarction in Swine?

Abstract

ObjectiveWe previously demonstrated that allogeneic cardiosphere‐derived cells (CDCs) improve myocardial function after infarction via paracrine effects when animals are pretreated with oral cyclosporine (CsA) prior to injury. The present study directly compared the efficacy of CDCs with and without CsA administered at the time of reperfusion after acute myocardial infarction (AMI) in a 3‐armed, blinded pre‐clinical study.MethodsStudies were completed in closed‐chest, propofol‐anesthetized swine (n=29). After assessing baseline hemodynamics, the LAD artery was occluded with a balloon catheter for 90 minutes and contrast‐enhanced cardiac CT performed to assess the area‐at‐risk (AAR). Thirty minutes after reperfusion, animals were randomized to receive a global intracoronary infusion of saline, CDCs (20×106 cells), or CDCs with CsA (2.5 mg/kg, iv; 200 mg, po qd). LV function and TTC infarct size (IS) were assessed 1 month later.ResultsBaseline hemodynamics and LV function were similar between groups. There was no difference between the CT AAR (% of LV mass; Saline: 22.2±1.0%, CDC: 23.7±0.7%, CDC+CsA: 24.7±1.4%, p=0.26). Infarct size was not different between groups (% of LV mass; Saline: 6.7±0.7%, CDC: 6.7±0.3%, CDC+CsA: 6.9±0.6%, p=0.95), or when normalized to risk area (% of AAR; Saline: 46.2±4.0%, CDC: 46.4±2.1%, CDC+CsA: 49.2±3.1%, p=0.79). There was no difference in CT ejection fraction (Saline: 49±2% vs. CDC: 46±2% vs. CDC+CsA: 47±2%, p=0.72). Wall thickening by echocardiography in the LAD‐perfused (Saline: 26±8% vs. CDC: 18±4% vs. CDC+CsA: 18±5%, p=0.56) and the remote, non‐infarcted (Saline: 100±7% vs. CDC: 111±10% vs. CDC+CsA: 119±11%, p=0.40) areas of the LV were also similar between groups.ConclusionGlobal infusion of allogeneic CDCs in the absence of CsA immunosuppression does not reduce chronic myocardial infarct size nor improve global or regional measures of LV function. Surprisingly, CDC therapy with IV CsA administered at the time of reperfusion does not appear to elicit previously demonstrated reparative effects. These data indicate that oral CsA pretreatment may be required to effect improved LV function with global intracoronary CDC therapy.Support or Funding InformationSupported by the National Heart Lung and Blood Institute (HL‐061610), the American Heart Association (17SDG33660200), the National Center for Advancing Translational Sciences (UL1TR001412), the Department of Veterans Affairs (1IO1BX002659), the New York State Department of Health (NYSTEM CO24351), and the Albert and Elizabeth Rekate Fund in Cardiovascular Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.