Poly (ADP-ribose) polymerase inhibition improves safe cardiac preservation times and cardiac function during heart transplantation

Objectives: Recently we showed, that the inhibition of the nuclear enzyme poly-ADP-ribose polymerase (PARP) reduces ischemia/reperfusion injury after cardioplegic arrest. In the present study, we investigated whether PARP inhibition is able to prolong safe cardiac preservation time and cardiac function in a rat heart transplantation model.

Methods: Intraabdominal heterotopic transplantation was performed in Lewis rats. After 4, 8 and 24 hours of ischemic preservation, reperfusion was started after application of either saline vehicle, or PJ34 (5mg/kg) a selective PARP-inhibitor (n=6/each group). Graft survival, coronary blood flow (CBF), left ventricular pressure (LVP), dP/dt, end-diastolic pressure (LVEDP), endothelium-dependent vasodilatation to acetylcholine (ACH) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were measured after one and 24 hours of reperfusion.

Results: 24h graft survival was significantly improved by PJ34 (8h preservation: 6/6 vs. 3/6 and 24h preservation: 6/6 vs. 0/6). After 4-hour preservation and 1-hour reperfusion, CBF (3.91±0.35 vs. 1.77±0.25, ml/min/g, p<0.05), LVP (101±10 vs. 67±8mmHg, p<0.05) and dP/dt (31902±522 vs. 1300±209mmHg/s, p<0.05) were significantly higher in PJ34 group in comparison to control. Vasodilatatory response to SNP was similar in both groups. ACH resulted in a significantly higher increase in CBF in the PJ34 group (71±8% vs. 22±6%, p<0.05). Functional differences were more pronounced between the remaining control and the PJ34 treated animals after 8 hours of preservation.

Conclusions: Thus, PARP inhibition significantly improves safe cardiac preservation times and reduces myocardial and endothelial dysfunction during early reperfusion after heart transplantation.