The Epicardial Delivery of Cardiosphere Derived Cells or Their Extracellular Vesicles is Safe but of Limited Value in Experimental Infarction

Overview

Journal Sci Rep

Specialty Science

Date 2021 Nov 13

PMID 34772964

Authors

Veronica Crisostomo

Claudia Baez-Diaz

Virginia Blanco-Blazquez

Veronica Alvarez

Esther Lopez-Nieto

Juan Maestre

Antoni Bayes-Genis

Carolina Galvez-Monton

Javier G Casado

Francisco M Sanchez-Margallo

Affiliations

Soon will be listed here.

Abstract

The epicardial administration of therapeutics via the pericardial sac offers an attractive route, since it is minimally invasive and carries no risks of coronary embolization. The aim of this study was to assess viability, safety and effectiveness of cardiosphere-derived cells (CDCs), their extracellular vesicles (EVs) or placebo administered via a mini-thoracotomy 72 h after experimental infarction in swine. The epicardial administration was completed successfully in all cases in a surgery time (knife-to-skin) below 30 min. No significant differences between groups were found in cardiac function parameters evaluated using magnetic resonance imaging before therapy and at the end of the study, despite a trend towards improved function in CDC-treated animals. Moreover, infarct size at 10 weeks was smaller in treated animals, albeit not significantly. Arrhythmia inducibility did not differ between groups. Pathological examination showed no differences, nor were there any pericardial adhesions evidenced in any case 10 weeks after surgery. These results show that the epicardial delivery of CDCs or their EVs is safe and technically easy 3 days after experimental myocardial infarction in swine, but it does not appear to have any beneficial effect on cardiac function. Our results do not support clinical translation of these therapies as implemented in this work.

References

Bolli R . Repeated Cell Therapy: A Paradigm Shift Whose Time Has Come. Circ Res. 2017; 120(7):1072-1074. PMC: 5384469. DOI: 10.1161/CIRCRESAHA.117.310710. View

Malliaras K, Smith R, Kanazawa H, Yee K, Seinfeld J, Tseliou E . Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. Circulation. 2013; 128(25):2764-75. PMC: 3907064. DOI: 10.1161/CIRCULATIONAHA.113.002863. View

Fu Y, Azene N, Ehtiati T, Flammang A, Gilson W, Gabrielson K . Fused X-ray and MR imaging guidance of intrapericardial delivery of microencapsulated human mesenchymal stem cells in immunocompetent swine. Radiology. 2014; 272(2):427-37. PMC: 4197996. DOI: 10.1148/radiol.14131424. View

Xiao Y, Sigg D, Ujhelyi M, Wilhelm J, Richardson E, Iaizzo P . Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias. Am J Physiol Heart Circ Physiol. 2008; 294(5):H2212-8. DOI: 10.1152/ajpheart.91502.2007. View

Lopez E, Marinaro F, de Pedro M, Sanchez-Margallo F, Gomez-Serrano M, Ponath V . The Immunomodulatory Signature of Extracellular Vesicles From Cardiosphere-Derived Cells: A Proteomic and miRNA Profiling. Front Cell Dev Biol. 2020; 8:321. PMC: 7295954. DOI: 10.3389/fcell.2020.00321. View

Gallet R, Dawkins J, Valle J, Simsolo E, de Couto G, Middleton R . Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J. 2017; 38(3):201-211. PMC: 5837390. DOI: 10.1093/eurheartj/ehw240. View

Govea A, Lee R . Pericardial Delivery of Biological Agents: The Next Frontier?. JACC Basic Transl Sci. 2018; 2(5):610-612. PMC: 6058951. DOI: 10.1016/j.jacbts.2017.09.007. View

Aldridge V, Garg A, Davies N, Bartlett D, Youster J, Beard H . Human mesenchymal stem cells are recruited to injured liver in a β1-integrin and CD44 dependent manner. Hepatology. 2012; 56(3):1063-73. DOI: 10.1002/hep.25716. View

Garcia J, Campbell P, Kumar G, Langberg J, Cesar L, Wang L . A Minimally Invasive, Translational Method to Deliver Hydrogels to the Heart Through the Pericardial Space. JACC Basic Transl Sci. 2018; 2(5):601-609. PMC: 6058920. DOI: 10.1016/j.jacbts.2017.06.003. View

10.

Frangogiannis N . The Extracellular Matrix in Ischemic and Nonischemic Heart Failure. Circ Res. 2019; 125(1):117-146. PMC: 6588179. DOI: 10.1161/CIRCRESAHA.119.311148. View

11.

Lopez E, Blazquez R, Marinaro F, Alvarez V, Blanco V, Baez C . The Intrapericardial Delivery of Extracellular Vesicles from Cardiosphere-Derived Cells Stimulates M2 Polarization during the Acute Phase of Porcine Myocardial Infarction. Stem Cell Rev Rep. 2019; 16(3):612-625. PMC: 7253530. DOI: 10.1007/s12015-019-09926-y. View

12.

Weil B, Suzuki G, Leiker M, Fallavollita J, Canty Jr J . Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium. Circ Res. 2015; 117(7):634-44. PMC: 4567914. DOI: 10.1161/CIRCRESAHA.115.306850. View

13.

Gyongyosi M, Wojakowski W, Lemarchand P, Lunde K, Tendera M, Bartunek J . Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ Res. 2015; 116(8):1346-60. PMC: 4509791. DOI: 10.1161/CIRCRESAHA.116.304346. View

14.

Kolettis T, Kazakos N, Katsouras C, Niokou D, Pappa L, Koulouras V . Intrapericardial drug delivery: pharmacologic properties and long-term safety in swine. Int J Cardiol. 2005; 99(3):415-21. DOI: 10.1016/j.ijcard.2004.03.004. View

15.

Smetana G, Lawrence V, Cornell J . Preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med. 2006; 144(8):581-95. DOI: 10.7326/0003-4819-144-8-200604180-00009. View

16.

Sousonis V, Sfakianaki T, Ntalianis A, Nanas I, Kontogiannis C, Aravantinos D . 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. J Cardiovasc Pharmacol Ther. 2020; 26(1):88-99. DOI: 10.1177/1074248420941672. View

17.

Richardson E, Rolfes C, Woo O, Elmquist W, Benditt D, Iaizzo P . Cardiac responses to the intrapericardial delivery of metoprolol: targeted delivery compared to intravenous administration. J Cardiovasc Transl Res. 2011; 5(4):535-40. DOI: 10.1007/s12265-011-9315-x. View

18.

Kanazawa H, Tseliou E, Malliaras K, Yee K, Dawkins J, de Couto G . Cellular postconditioning: allogeneic cardiosphere-derived cells reduce infarct size and attenuate microvascular obstruction when administered after reperfusion in pigs with acute myocardial infarction. Circ Heart Fail. 2015; 8(2):322-32. PMC: 4366297. DOI: 10.1161/CIRCHEARTFAILURE.114.001484. View

19.

Gabriel A, Martinsson A, Wretlind B, Ahnve S . IL-6 levels in acute and post myocardial infarction: their relation to CRP levels, infarction size, left ventricular systolic function, and heart failure. Eur J Intern Med. 2005; 15(8):523-528. DOI: 10.1016/j.ejim.2004.07.013. View

20.

Ridker P, Rifai N, Stampfer M, Hennekens C . Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101(15):1767-72. DOI: 10.1161/01.cir.101.15.1767. View