John Onsy Louca , Magnus Althage , Marco Öchsner , Aravinda Page , Joao Pedro Nunes , Catherine Wilson , Sanjay Sinha , Simon Messer , James Matt Bae , Mostin Hu , Nicole Asemota , Sarah Fielding , Sai Bhagra , Neil Henderson , Johnny Lindquist , Daniela Später , Anna Collén , Kaushik Sengupta , Benjamin Challis , Justin Perkins , Stephen Large
{"title":"非原位心脏灌注：一个测试人类心脏心血管治疗的新平台","authors":"John Onsy Louca , Magnus Althage , Marco Öchsner , Aravinda Page , Joao Pedro Nunes , Catherine Wilson , Sanjay Sinha , Simon Messer , James Matt Bae , Mostin Hu , Nicole Asemota , Sarah Fielding , Sai Bhagra , Neil Henderson , Johnny Lindquist , Daniela Später , Anna Collén , Kaushik Sengupta , Benjamin Challis , Justin Perkins , Stephen Large","doi":"10.1016/j.jhlto.2025.100336","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Explanted hearts from recipients undergoing cardiac transplantation may be utilized as a human model of cardiomyopathy. Ex-situ perfusion of hearts allows control of the physiological and biochemical conditions of perfusion. <em>AZD8601 is</em> a novel modRNA for VEGF-A that was shown to be safe in a Phase IIa clinical trial – the EPICCURE trial. This proof-of-concept study aimed to demonstrate the potential utility of testing novel therapies on explanted recipient hearts using ex situ machine perfusion.</div></div><div><h3>Methods</h3><div>In order to ascertain the expression of VEGF-A in a human model of cardiomyopathy, <em>AZD8601</em> was injected at high- and low-dose into the mid-myocardium of the left ventricle of human hearts explanted at the time of cardiac transplantation and perfused on the m0rgan, a novel, normothermic organ perfusion machine. Hearts were perfused ex situ for 6 h. After which, injection sites were biopsied and divided into subendocardium, mid-myocardium and sub-epicardial myocardium. Immuno-analysis was performed to assess levels of VEGF-A protein.</div></div><div><h3>Results</h3><div>There were elevated levels of VEGF-A protein in the subendocardium and mid-myocardium of injection sites which received <em>AZD8601</em>. Low-dose and high-dose <em>AZD8601</em> resulted in a significantly higher concentration of VEGF-A protein in the myocardium.</div></div><div><h3>Conclusions</h3><div>This study builds on the EPICCURE study, a phase IIa clinical trial which demonstrated safety of this mRNA in patients undergoing coronary artery bypass grafting. This study provides a novel model of diseased human heart for experimental studies utilizing ex situ heart perfusion.</div></div>","PeriodicalId":100741,"journal":{"name":"JHLT Open","volume":"9 ","pages":"Article 100336"},"PeriodicalIF":0.0000,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ex situ heart perfusion: A novel platform to test cardiovascular therapeutics in human hearts\",\"authors\":\"John Onsy Louca , Magnus Althage , Marco Öchsner , Aravinda Page , Joao Pedro Nunes , Catherine Wilson , Sanjay Sinha , Simon Messer , James Matt Bae , Mostin Hu , Nicole Asemota , Sarah Fielding , Sai Bhagra , Neil Henderson , Johnny Lindquist , Daniela Später , Anna Collén , Kaushik Sengupta , Benjamin Challis , Justin Perkins , Stephen Large\",\"doi\":\"10.1016/j.jhlto.2025.100336\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Explanted hearts from recipients undergoing cardiac transplantation may be utilized as a human model of cardiomyopathy. Ex-situ perfusion of hearts allows control of the physiological and biochemical conditions of perfusion. <em>AZD8601 is</em> a novel modRNA for VEGF-A that was shown to be safe in a Phase IIa clinical trial – the EPICCURE trial. This proof-of-concept study aimed to demonstrate the potential utility of testing novel therapies on explanted recipient hearts using ex situ machine perfusion.</div></div><div><h3>Methods</h3><div>In order to ascertain the expression of VEGF-A in a human model of cardiomyopathy, <em>AZD8601</em> was injected at high- and low-dose into the mid-myocardium of the left ventricle of human hearts explanted at the time of cardiac transplantation and perfused on the m0rgan, a novel, normothermic organ perfusion machine. Hearts were perfused ex situ for 6 h. After which, injection sites were biopsied and divided into subendocardium, mid-myocardium and sub-epicardial myocardium. Immuno-analysis was performed to assess levels of VEGF-A protein.</div></div><div><h3>Results</h3><div>There were elevated levels of VEGF-A protein in the subendocardium and mid-myocardium of injection sites which received <em>AZD8601</em>. Low-dose and high-dose <em>AZD8601</em> resulted in a significantly higher concentration of VEGF-A protein in the myocardium.</div></div><div><h3>Conclusions</h3><div>This study builds on the EPICCURE study, a phase IIa clinical trial which demonstrated safety of this mRNA in patients undergoing coronary artery bypass grafting. This study provides a novel model of diseased human heart for experimental studies utilizing ex situ heart perfusion.</div></div>\",\"PeriodicalId\":100741,\"journal\":{\"name\":\"JHLT Open\",\"volume\":\"9 \",\"pages\":\"Article 100336\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-07-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JHLT Open\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2950133425001314\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JHLT Open","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2950133425001314","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Ex situ heart perfusion: A novel platform to test cardiovascular therapeutics in human hearts
Background
Explanted hearts from recipients undergoing cardiac transplantation may be utilized as a human model of cardiomyopathy. Ex-situ perfusion of hearts allows control of the physiological and biochemical conditions of perfusion. AZD8601 is a novel modRNA for VEGF-A that was shown to be safe in a Phase IIa clinical trial – the EPICCURE trial. This proof-of-concept study aimed to demonstrate the potential utility of testing novel therapies on explanted recipient hearts using ex situ machine perfusion.
Methods
In order to ascertain the expression of VEGF-A in a human model of cardiomyopathy, AZD8601 was injected at high- and low-dose into the mid-myocardium of the left ventricle of human hearts explanted at the time of cardiac transplantation and perfused on the m0rgan, a novel, normothermic organ perfusion machine. Hearts were perfused ex situ for 6 h. After which, injection sites were biopsied and divided into subendocardium, mid-myocardium and sub-epicardial myocardium. Immuno-analysis was performed to assess levels of VEGF-A protein.
Results
There were elevated levels of VEGF-A protein in the subendocardium and mid-myocardium of injection sites which received AZD8601. Low-dose and high-dose AZD8601 resulted in a significantly higher concentration of VEGF-A protein in the myocardium.
Conclusions
This study builds on the EPICCURE study, a phase IIa clinical trial which demonstrated safety of this mRNA in patients undergoing coronary artery bypass grafting. This study provides a novel model of diseased human heart for experimental studies utilizing ex situ heart perfusion.
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