Cell-Permeable Succinate Improves Platelet Respiration in Patients Undergoing Cardiopulmonary Bypass: A Pilot Study

Abstract

Open-heart surgery with cardiopulmonary bypass (CPB) remains the standard approach for complex cardiac pathologies, such as advanced coronary heart disease and severe valvular defects. Platelet dysfunction has been widely reported, with both structural and functional changes being elicited by the CPB circuit. Succinate is a mitochondrial substrate that is metabolized through complex II (CII) but is impermeable to cellular membranes when given exogenously. Cell-permeable succinates are novel prodrugs developed to support mitochondrial electron transport (ET) and prevent energy depletion in various pathologies. The aim of the present pilot study was to investigate the role of NV118 (diacetoxymethyl succinate), a cell-permeable succinate, on platelet respiration in a pilot group of patients undergoing CPB. Blood samples (20 mL) were collected from participants before (prior to heparin administration) and after CPB (within 10 min after protamine sulphate administration). Platelets were isolated through a two-step centrifugation protocol. Mitochondrial respiration was analyzed by means of high-resolution respirometry in the presence of NV118 or its solvent (DMSO). The main respiratory parameters recorded were as follows: ROUTINE respiration, LEAK respiration, and maximal uncoupled respiration for both CI and CII (ET capacity) and for CII solely after CI inhibition (ET CII capacity). Here, we report that NV118 elicited a global increase in platelet respiration both pre- and post-CPB. In conclusion, NV118, a cell-permeable succinate, improved platelet bioenergetics in the setting of cardiopulmonary bypass. Whether the compound can support platelet function and/or provide organ protection at the mitochondrial level during CPB are clearly worthy and important areas for future investigation.