The Cardio-protective Efficacy of Cardioplegic Solution Supplemented with Sildenafil in Neonatal Pig Model of Cardiopulmonary Bypass and Cardioplegic Arrest

Abstract

The development of the cardiopulmonary bypass machine and cardioplegia has made the repair of congenital cardiac lesions safe and reproducible. However, congenital cardiac surgery is still associated with significant morbidity and mortality. This is associated with a low cardiac output state due to ischaemia/reperfusion (IR) injury. This could be ameliorated by improvement in methods of myocardial protection.
Sildenafil, a phosophodiesterase 5 inhibitor, has been shown to have cardioprotective properties in animal studies at clinically relevant concentrations. However, there have been no studies investigating the role of Sildenafil in IR injury prevention in a large animal model of the immature heart.
We have established a swine model, using two groups, that weighed 10kg (n=31) and 20kg (n=55) reflecting two stages of development. The pigs were put on cardiopulmonary bypass (CPB) and subjected to 60 minutes ischaemia using cardioplegia solution, followed by 20 minutes reperfusion on CPB, weaned off CPB, and eventually terminated at 60 minutes of reperfusion. The cardioplegia treatment arms were control (St Thomas solution) (n=39), 10 nM Sildenafil (n=25) and 70 nM Sildenafil (n=22). We collected blood samples prior to CPB, before ischaemia, at the end of cardioplegic arrest, during reperfusion on CPB, and off CPB to measure cTnI. Left ventricular biopsies were obtained before cross clamp application, at the end of ischaemia, during reperfusion on CPB, and just prior to termination off CPB to evaluate high energy metabolites.
We have demonstrated that cold blood cardioplegia (4C) was associated with higher rate of weaning off CPB and a lower rate of reperfusion arrhythmia (p<0.05). Furthermore, Sildenafil was associated with better ATP recovery and energy preservation (p<0.05).
In conclusion, Sildenafil is a promising cardioprotective agent that can be used as an adjunct to standard cardioplegia solutions. We aim at performing further translational research using this model as a step towards a clinical trial in humans.

Date of Award	4 Feb 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Saadeh Suleiman (Supervisor) & Massimo Caputo (Supervisor)