The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs

Abstract

Connexin 43 is located in the cardiomyocyte sarcolemma and in the mitochondrial membrane. Sarcolemmal connexin 43 contributes to the spread of myocardial ischemia/reperfusion injury, whereas mitochondrial connexin 43 contributes to cardioprotection. We have now investigated the antiarrhythmic dipeptide ZP1609 (danegaptide), which is an analog of the connexin 43 targeting antiarrhythmic peptide rotigaptide (ZP123), in an established and clinically relevant experimental model of ischemia/reperfusion in pigs. Pigs were subjected to 60 min coronary occlusion and 3 h reperfusion. ZP1609 (n = 10) was given 10 min prior to reperfusion (75 μg/kg b.w. bolus i.v. + 57 μg/kg/min i.v. infusion for 3 h). Immediate full reperfusion (IFR, n = 9) served as control. Ischemic postconditioning (PoCo, n = 9; 1 min LAD reocclusion after 1 min reperfusion; four repetitions) was used as a positive control of cardioprotection. Infarct size (TTC) was determined as the end point of cardioprotection. Systemic hemodynamics and regional myocardial blood flow during ischemia were not different between groups. PoCo and ZP1609 reduced infarct size vs. IFR (IFR, 46 ± 4 % of area at risk; mean ± SEM; PoCo, 31 ± 4 %; ZP1609, 25 ± 5 %; both p < 0.05 vs. IFR; ANOVA). There were only few arrhythmias during reperfusion such that no antiarrhythmic action of ZP1609 was observed. ZP1609 when given before reperfusion reduces infarct size to a similar extent as ischemic postconditioning. Further studies are necessary to define the mechanism/action of ZP1609 on connexin 43 in cardiomyocytes.

Effects of Rotigaptide and RIC on Ischemia Reperfusion Injury in the In Vitro Rabbit Heart

“…The absence in change of hemodynamic recovery in our study is in accordance with previous studies testing Rotigaptide and the new analogue danegaptide [1][2][3][4][5][6][7][8][9][10][11][12][13]20,[42][43][44]. Although we did not observe statistically significant changes in post-ischemic hemodynamic outcome between the different groups the pattern followed the expected responses according to infarct size reduction.…”

“…In this study, IS reduction was dose-dependent [12]. More recently, danegaptide a mimetic of the connexin 43 targeting peptide Rotigaptide also demonstrated cardioprotective capacity in an in vivo model [20].…”

Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial

“…The trial was adequately sized for its purpose. The primary endpoint, MSI by CMR, did not differ between treatment groups, and therefore, in this clinical proof-of-concept trial, we were not able to confirm results from promising preclinical experiments 8. In STEMI, reperfusion may in itself jeopardise the myocardium,14 and therefore, a relevant cardioprotective strategy should reduce cardiomyocyte damage and increase salvage.…”

“…The selection of doses was based on extrapolation of the efficacious doses in a porcine model of ischaemia reperfusion injury8 and modelling using pharmacokinetic parameters obtained from two phase 1 trials with danegaptide (data not published). The duration of infusion was 6 hours to allow continuous exposure during the PCI procedure and the first hours after revascularisation to optimise chances of tissue salvage.…”

“…The dipeptide danegaptide increases gap junctional conductance by interaction with connexin-43 7. It reduces myocardial infarct sizes in dogs and pigs ischaemia reperfusion models 8. Therefore, danegaptide could be a relevant candidate to address reperfusion injury in human 9…”