Intracoronary Administration of Allogeneic Cardiosphere-Derived Cells Immediately Prior to Reperfusion in Pigs With Acute Myocardial Infarction Reduces Infarct Size and Attenuates Adverse Cardiac Remodeling

Abstract

Background: Allogeneic cardiosphere-derived cells (CDCs) exert cardioprotective effects when administered intracoronarily after reperfusion in animal models of acute myocardial infarction (AMI). The “no-reflow” phenomenon develops rapidly post-reperfusion and may undermine the efficacy of cell therapy, due to poor cell delivery in areas of microvascular obstruction (MVO). We hypothesized that CDC-induced cardioprotection would be enhanced by cell administration prior to reperfusion, when microvasculature is still relatively intact, to facilitate widespread cell delivery within the ischemic area. Methods and Results: We studied 81 farm pigs; 55 completed the specified protocols. A dose-optimization study in infarcted pigs demonstrated that the doses of 5 million and 10 million CDCs are the maximum safe doses that can be administered intracoronarily at 5 minutes prior to and at 5 minutes post-reperfusion, respectively, without aggravating MVO. Quantification of acute cell retention by polymerase chain reaction demonstrated that cell delivery prior to reperfusion resulted in higher cardiac cell retention compared to delivery post-reperfusion. We then performed a randomized, placebo-controlled study to assess the long-term efficacy of intracoronary infusion of 5 million allogeneic CDCs, delivered at 5 minutes prior to reperfusion, in a porcine model of AMI. The CDC therapy resulted in decreased scar size, improved regional systolic function, and attenuation of adverse cardiac remodeling (manifested as preserved global systolic function, preserved end-systolic volume, and decreased interstitial fibrosis) compared to placebo at 30 days post-MI. Conclusions: Dose-optimized intracoronary infusion of allogeneic CDCs prior to reperfusion in a porcine model of AMI is feasible, safe and confers long-term benefits.

The epicardial delivery of cardiosphere derived cells or their extracellular vesicles is safe but of limited value in experimental infarction

“…As a way to bypass this limitation and being able to administer therapy early after infarction, several studies exploring the intrapericardial route have established its feasibility and overall safety post myocardial infarction 7 , 14 – 18 , with other studies also exploring antiarrhythmic potential of this route 19 . While the intracoronary route is generally well tolerated, our own studies 20 proved that it may be harmful when applied on the same day as experimental myocardial induction, despite other groups experiences to the contrary 8 , 21 . Moreover, early after infarction the existence of no-reflow may compromise cell delivery to the target areas if using the intravascular route beyond the first hour after reperfusion 21 .…”

“…While the intracoronary route is generally well tolerated, our own studies 20 proved that it may be harmful when applied on the same day as experimental myocardial induction, despite other groups experiences to the contrary 8 , 21 . Moreover, early after infarction the existence of no-reflow may compromise cell delivery to the target areas if using the intravascular route beyond the first hour after reperfusion 21 .…”

Epicardial Delivery of Cardiosphere Derived Cells or Their Extracellular Vesicles in a Relevant Infarcted Swine Model: Safe, Easy but of Limited Effectiveness.

“…As a way to bypass this limitation and being able to administer therapy early after infarction, several studies exploring the intrapericardial route have established its feasibility and overall safety post myocardial infarction [7,[14][15][16][17][18], with other studies also exploring antiarrhythmic potential of this route [19]. While the intracoronary route is generally well tolerated, our own studies [20] proved that it may be harmful when applied on the same day as experimental myocardial induction, despite other groups experiences to the contrary [8,21]. Moreover, early after infarction the existence of no-re ow may compromise cell delivery to the target areas if using the intravascular route beyond the rst hour after reperfusion [21].…”

“…While the intracoronary route is generally well tolerated, our own studies [20] proved that it may be harmful when applied on the same day as experimental myocardial induction, despite other groups experiences to the contrary [8,21]. Moreover, early after infarction the existence of no-re ow may compromise cell delivery to the target areas if using the intravascular route beyond the rst hour after reperfusion [21].…”

Epicardium-Derived Tbx18+ CDCs Transplantation Improve Heart Function in Infarcted Mice

“…Moreover, the Halt cardiomyOPathy progrEssion (HOPE)-Duchenne trial assessed feasibility, safety, and efficacy of intracoronary allogeneic CDCs (CAP-1002) in patients with Duchenne muscular dystrophy (DMD) ( 17 ). Although accumulating evidence demonstrated that CDCs graft contributed to the heart function improvement and inflammation inhibition ( 18 – 20 ) and little is known about origin of these cells. Conventional CDCs from heart biopsy are composed of a mixture of epicardium-, myocardium-, and endocardium-derived subpopulations.…”