Abstract
While heart transplantation (HTX) is the definitive therapy of heart failure, donor shortage is emerging. Pharmacological activation of soluble guanylate cyclase (sGC) and increased cGMP-signalling have been reported to have cardioprotective properties. Gemfibrozil has recently been shown to exert sGC activating effects in vitro. We aimed to investigate whether pharmacological preconditioning of donor hearts with gemfibrozil could protect against ischemia/reperfusion injury and preserve myocardial function in a heterotopic rat HTX model. Donor Lewis rats received p.o. gemfibrozil (150 mg/kg body weight) or vehicle for 2 days. The hearts were explanted, stored for 1 h in cold preservation solution, and heterotopically transplanted. 1 h after starting reperfusion, left ventricular (LV) pressure-volume relations and coronary blood flow (CBF) were assessed to evaluate early post-transplant graft function. After 1 h reperfusion, LV contractility, active relaxation and CBF were significantly (p < 0.05) improved in the gemfibrozil pretreated hearts compared to that of controls. Additionally, gemfibrozil treatment reduced nitro-oxidative stress and apoptosis, and improved cGMP-signalling in HTX. Pharmacological preconditioning with gemfibrozil reduces ischemia/reperfusion injury and preserves graft function in a rat HTX model, which could be the consequence of enhanced myocardial cGMP-signalling. Gemfibrozil might represent a useful tool for cardioprotection in the clinical setting of HTX surgery soon.
Highlights
While heart transplantation (HTX) is the definitive therapy of heart failure, donor shortage is emerging
Increased oxidative stress during ischemia/reperfusion leads to the oxidation of soluble guanylate cyclase (sGC), thereby impairing its activity and responsiveness to endogenous nitric oxide (NO), which mechanism could result in the deterioration of the cyclic guanosine monophosphate (cGMP) signalling cascade[7]
Gemfibrozil treatment led to a similar improvement in diastolic function at higher preload volumes, resulting in significantly (p < 0.05) increased dP/dtmin values compared to HTX, reflecting better myocardial relaxation (Fig. 1C)
Summary
While heart transplantation (HTX) is the definitive therapy of heart failure, donor shortage is emerging. Pharmacological activation of soluble guanylate cyclase (sGC) and increased cGMP-signalling have been reported to have cardioprotective properties. We aimed to investigate whether pharmacological preconditioning of donor hearts with gemfibrozil could protect against ischemia/reperfusion injury and preserve myocardial function in a heterotopic rat HTX model. Pharmacological preconditioning with gemfibrozil reduces ischemia/reperfusion injury and preserves graft function in a rat HTX model, which could be the consequence of enhanced myocardial cGMP-signalling. Ischemia/reperfusion injury is one of the major determinants of primary graft failure and long-term outcome in HTX1 Possible prevention of such an injury can be achieved by a professional transplant team with efficient logistics, developing surgical techniques and novel cardioplegic solutions[2]. Increased oxidative stress during ischemia/reperfusion leads to the oxidation of sGC, thereby impairing its activity and responsiveness to endogenous NO, which mechanism could result in the deterioration of the cGMP signalling cascade[7]
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