Pharmacology, pharmacogenomics, drug discovery and design, drug therapy
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.
