Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model

Claudia Báez-Díaz,Carolina Gálvez-Montón,Antoni Bayes-Genis,Irene González,Ana Abad,Belén Sánchez,Rob Steendam,Francisco-Miguel Sánchez-Margallo,Virginia Blanco-Blázquez,Itziar Palacios,Verónica Crisóstomo,Okke Franssen

doi:10.1038/s41598-020-64097-y

Abstract

Insulin-like growth factor-1 (IGF-1) has demonstrated beneficial effects after myocardial infarction (MI). Microencapsulation of IGF-1 could potentially improve results. We aimed to test the effect of an intracoronary (IC) infusion of microencapsulated IGF-1 in a swine acute MI model. For that purpose IC injection of a 10 ml solution of 5 × 106 IGF-1 loaded microspheres (MSPs) (n = 8, IGF-1 MSPs), 5 × 106 unloaded MSPs (n = 9; MSPs) or saline (n = 7; CON) was performed 48 hours post-MI. Left ventricular ejection fraction (LVEF), indexed ventricular volumes and infarct size (IS) were determined by cardiac magnetic resonance at pre-injection and 10 weeks. Animals were euthanized at 10 weeks, and myocardial fibrosis and vascular density were analysed. End-study LVEF was significantly greater in IGF-1 MSPs compared to MSPs and CON, while ventricular volumes exhibited no significant differences between groups. IS decreased over time in all groups. Collagen volume fraction on the infarct area was significantly reduced in IGF-1 MSPs compared to CON and MSPs. Vascular density analysis of infarct and border zones showed no significant differences between groups. In conclusion, the IC injection of 5 × 106 IGF-1 loaded MSPs in a porcine acute MI model successfully improves cardiac function and limits myocardial fibrosis, which could be clinically relevant.

Highlights

Cardiovascular diseases, especially ischemic heart disease, are the leading cause of mortality worldwide accounting for almost 4 million deaths a year in Europe[1,2]
Current research directions in regenerative cardiology are moving to a cell-less approach, since it is known that stem cells are able to secrete combinations of biomolecules that modulate the composition of the damaged cardiac environment contributing to functional tissue repair by stimulating the migration, proliferation and survival of endogenous cardiac progenitor cells[8,9], as well as attenuating fibrosis and modulating inflammation[10,11]
We demonstrated a clear improvement in cardiac function, reflected by better Left ventricular ejection fraction (LVEF) and ESVi, along with lower collagen volume fraction (CVF) and higher vascular density

Summary

Introduction

Cardiovascular diseases, especially ischemic heart disease, are the leading cause of mortality worldwide accounting for almost 4 million deaths a year in Europe[1,2] Conventional treatments such as angioplasty and coronary stenting have contributed to reduce early mortality after an acute myocardial infarction (MI)[3]. Several studies suggest that the beneficial effect of stem cells does not lie in their multiplication, but in their paracrine actions[7] Based on this insight, current research directions in regenerative cardiology are moving to a cell-less approach, since it is known that stem cells are able to secrete combinations of biomolecules that modulate the composition of the damaged cardiac environment contributing to functional tissue repair by stimulating the migration, proliferation and survival of endogenous cardiac progenitor cells (eCSCs)[8,9], as well as attenuating fibrosis and modulating inflammation[10,11]. 400 mg from 5 days prior to infarction to 3 days after it 500 mg from 24 hours before model induction continuing until euthanasia

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