Quantitative Hybrid Cardiac [18F]FDG-PET-MRI Images for Assessment of Cardiac Repair by Preconditioned Cardiosphere-Derived Cells

Johannes Winkler,Dominika Lukovic,Julia Mester-Tonczar,Katrin Zlabinger,Alfred Gugerell,Noemi Pavo,András Jakab,Zsuzsanna Szankai,Denise Traxler,Claudia Müller,Andreas Spannbauer,Martin Riesenhuber,Ena Hašimbegović,James Dawkins,Matthias Zimmermann,Hendrik J Ankersmit,Eduardo Marbán,Mariann Gyöngyösi

doi:10.1016/j.omtm.2020.06.008

Abstract

Cardiosphere-derived cells (CDCs) are progenitor cells derived from heart tissue and have shown promising results in preclinical models. APOSEC, the secretome of irradiated peripheral blood mononuclear cells, has decreased infarct size in acute and chronic experimental myocardial infarction (MI). We enhanced the effect of CDCs with APOSEC preconditioning (apoCDC) and investigated the reparative effect in a translational pig model of reperfused MI. Supernatants of CDCs, assessed by proteomic analysis, revealed reduced production of extracellular matrix proteins after in vitro APOSEC preconditioning. In a porcine model of catheter-based reperfused anterior acute MI (AMI), CDCs with (apoCDC, n = 8) or without APOSEC preconditioning (CDC, n = 6) were infused intracoronary, 15 min after the start of reperfusion. Untreated AMI animals (n = 7) and sham procedures (n = 5) functioned as controls. 2-deoxy-2-(18 F)-fluoro-D-glucose-positron emission tomography-magnetic resonance imaging ([18F]FDG-PET-MRI), with late enhancement after 1 month, showed reduced scar volume and lower transmurality of the infarcted area in CDC and apoCDC compared to AMI controls. Segmental quantitative PET images displayed indicated more residual viability in apoCDC. The left-ventricle (LV) ejection fraction was improved nonsignificantly to 45.8% ± 8.6% for apoCDC and 43.5% ± 7.1% for CDCs compared to 38.5% ± 4.4% for untreated AMI. Quantitative hybrid [18F]FDG-PET-MRI demonstrated improved metabolic and functional recovery after CDC administration, whereas apoCDCs induced preservation of viability of the infarcted area.

Highlights

After almost 20 years of intense research and recent setbacks in clinical evaluations, the utility, risks, and efficacy of intracoronary cell administration are controversially debated.[1,2] The main, generally accepted mechanism of eventual improvement in cardiac function in experimental and some clinical studies is a paracrine effect caused by secreted factors.[3]
Coculture of APOSEC with Cardiosphere-derived cells (CDCs) Prevents Secretion of Extracellular Matrix (ECM) Proteins and Increases Expression and Secretion of Angiogenic and Homing Factors We investigated apoCDCs for maximizing the prosurvival and secretion-enhancing effects (Figure 1)
In a first step, we assessed the effect of APOSEC on CDC in vitro and examined the content of secretory proteins with or without APOSEC supplementation with a proteomic analysis

Summary

Introduction

After almost 20 years of intense research and recent setbacks in clinical evaluations, the utility, risks, and efficacy of intracoronary cell administration are controversially debated.[1,2] The main, generally accepted mechanism of eventual improvement in cardiac function in experimental and some clinical studies is a paracrine effect caused by secreted factors.[3]. Preclinical and clinical studies demonstrated that intracoronary delivery of allogeneic CDCs, directly after reperfusion of acute MI (AMI), is effective in cardioprotection, prevents microvascular obstruction, and attenuates adverse acute remodeling.[7,8]

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Conclusion