The IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): multicenter pig study on the effect of ischemic preconditioning

Abstract

Acute myocardial infarction; Ischemic preconditioning; Pig

Infarto agudo de miocardio; Preacondicionamiento isquémico; Cerdo

Infart agut de miocardi; Precondicionament isquèmic; Porc

Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has been largely disappointing. One reason for the lack of translation is the lack of rigor and reproducibility in pre-clinical studies. To address this, we have established the European IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) pig AMI network with centralized randomization and blinded core laboratory IS analysis and validated the network with ischemic preconditioning (IPC) as a positive control. Ten sites in the COST Innovators Grant (IG16225) network participated in the IMPACT network. Three sites were excluded from the final analysis through quality control of infarct images and use of pre-defined exclusion criteria. Using a centrally generated randomization list, pigs were allocated to myocardial ischemia/reperfusion (I/R, N = 5/site) or IPC + I/R (N = 5/site). The primary endpoint was IS [% area-at-risk (AAR)], as quantified by triphenyl-tetrazolium-chloride (TTC) staining in a centralized, blinded core laboratory (5 sites), or IS [% left-ventricular mass (LV)], as quantified by a centralized, blinded cardiac magnetic resonance (CMR) core laboratory (2 sites). In pooled analyses, IPC significantly reduced IS when compared to I/R (57 ± 14 versus 32 ± 19 [%AAR] N = 25 pigs/group; p < 0.001; 25 ± 13 versus 14 ± 8 [%LV]; N = 10 pigs/group; p = 0.021). In site-specific analyses, in 4 of the 5 sites, IS was significantly reduced by IPC when compared to I/R when quantified by TTC and in 1 of 2 sites when quantified by CMR. A pig AMI multicenter European network with centralized randomization and core blinded IS analysis was established and validated with the aim to improve the reproducibility of cardioprotective interventions in pre-clinical studies and the translation of cardioprotection for patient benefit.

Open Access funding enabled and organized by Projekt DEAL. DJH is supported by the Duke-NUS Signature Research Program funded by the Ministry of Health, Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator Award (MOH-STaR21jun-0003), Centre Grant scheme (NMRC CG21APR1006), and Collaborative Centre Grant scheme (NMRC/CG21APRC006). The Ministry for Innovation and Technology in Hungary provided funding to this study under the 2020–1.1.5-GYORSÍTÓSÁV call program (2020-1.1.5-GYORSÍTÓSÁV-2021-00011), also supported by project no. RRF-2.3.1-21-2022-00003 “National Heart Laboratory, Hungary” and by the Hungarian National Scientific Research Fund (OTKA-138223). CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation), and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/https://doi.org/10.13039/501100011033). GH and PK were supported by the German Research Foundation (CRC 1116 B8, RTG 2989) and EU COST Action METAHEART (CA 22169). VC is supported by the Instituto de Salud Carlos III (ISCIII, grant PI20/0247). AK and BKP are supported by the Ludwig Boltzmann Gesellschaft (CARREM). This article is based on work supported by the COST Actions EU-CARDIOPROTECTION CA16225 and IG16225.