CARDIOPROTECTIVE EFFECT OF ALLOGENEIC CARDIOSPHERE–DERIVED CELLS: REDUCTION OF INFARCT SIZE AND ATTENUATION OF NO–REFLOW WHEN ADMINISTERED IN THE INFARCT–RELATED ARTERY AFTER REPERFUSION IN PIGS WITH ACUTE MYOCARDIAL INFARCTION

SummaryPreinfarction angina and early reperfusion of the infarct-related artery are major determinants of reduced infarct-size in patients with acute myocardial infarction. The beneficial effects of preinfarction angina on infarct size have been attributed to the development of collateral vessels and/or to post-ischemic myocardial protection. However, recently, a relation has been found between prodromal angina, faster coronary recanalization, and smaller infarcts in patients treated with rt-PA: those with preinfarction angina showed earlier reperfusion (p = 0.006) and a 50% reduction of CKMB-estimated infarct-size (p = 0.009) compared to patients without preinfarction angina. This intriguing observation is consistent with a subsequent observation of higher coronary recanalization rates following thrombolysis in patients with prodromal preinfarction angina compared to patients without antecedent angina. Recent findings in dogs show an enhanced spontaneous lysis of plateletrich coronary thrombi with ischemic preconditioning, which is prevented by adenosine blockade, suggesting an antithrom-botic effect of ischemic metabolites. Understanding the mechanisms responsible for earlier and enhanced coronary recanalization in patients with preinfarction angina may open the way to new reperfusion strategies.A vast number of studies, globally involving ≈17,000 patients with acute myocardial infarction, have unequivocally shown that an infarction preceded by angina evolves into a smaller area of necrosis compared to an infarct not preceded by angina (Table 1) (1). So far, preinfarction angina has been thought to have cardioprotective effects mainly through two mechanisms: collateral perfusion of the infarctzone (2-4), and ischemic preconditioning of the myocardium (5-7). Here we discuss a further mechanism of protection represented by improved reperfusion of the infarct-related artery.

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Abstract 15656: Global Intracoronary Infusion of Allogeneic Cardiosphere-Derived Cells (CDCs) Immediately After Reperfusion Stimulates Myocyte Regeneration in Remote Viable Myocardium in Swine With Acute Myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.15656 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Gen Suzuki ◽

Brian R Weil ◽

Merced M Leiker ◽

Andrew Goelz ◽

James A Fallavollita ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Ejection Fraction ◽

Infarct Size ◽

Cell Size ◽

Remote Myocardium ◽

Viable Myocardium ◽

Nuclear Density ◽

Infarct Related Artery ◽

Myocyte Proliferation

Introduction: Previous studies evaluating regenerative strategies have focused on administering stem cells to the infarct related artery. Unfortunately, this does not stimulate cardiac regeneration nor prevent myocyte loss in viable remote myocardium that becomes dysfunctional due to LV remodeling. Hypothesis: We hypothesized that administrating allogeneic CDCs to the entire heart (global CDC infusion) at the time of reperfusion could improve function, stimulate myocyte regeneration and prevent myocyte loss throughout the LV. Methods: Yorkshire swine (n=12) underwent a one hour LAD occlusion. Ejection fraction (EF) decreased from 63 ± 2% at baseline to 44 ± 2% after infarction (p<0.05 vs. baseline). Immediately after reperfusion animals were randomized to allogeneic intracoronary CDCs or vehicle in a blinded fashion (n=6 each). Allogeneic CDCs (20 x 10^6 CDCs, cyclosporine 100 mg/day) were infused into the 3 major coronary distributions without interrupting flow. Four weeks later we assessed myocardial function (echo), myocyte proliferation (Ki67), infarct size (TTC), myocyte nuclear density and cell size in comparison to vehicle. Results: After 4 weeks, global CDC infusion increased wall thickening and ejection fraction despite the fact that infarct volume was not different (Table). CDCs stimulated myocyte proliferation (Ki67) in border and remote regions by 3-fold. As a result, myocyte number (nuclear density) increased by 34 % and cell size decreased by 7% in viable infarct border and remote regions. Conclusion: Global infusion of allogeneic CDCs immediately after reperfusion 1.) stimulates myocyte regeneration in viable myocardium remote from the infarct and 2.) improves regional and global LV function without altering infarct size. Thus, treating viable remote myocardium as well as the infarct related artery with allogeneic CDCs may afford a widely available approach to reverse LV dysfunction in patients with acute myocardial infarction.

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