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.

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Aortic stenosis is the most common valvular disease worldwide. Coronary artery disease (CAD) is often associated with degenerative aortic stenosis, particularly among older patients. Surgical treatment of the combined pathologies is highly recommended because the results are durable. Assessment of mitochondrial respiration in blood cells has recently emerged as a potential biomarker of the bioenergetic health but data regarding the changes in the setting of cardiopulmonary bypass (CPB) are scarce. A 67-year-old man was referred to the clinic for progressive breathlessness, constrictive thoracic pain and fatigue. Investigations revealed severe aortic stenosis and triple-vessel CAD. The aortic valve was replaced with a mechanical aortic prosthesis and coronary artery bypass graft was performed under mild hypothermia. We assessed platelet complex I (CI)- and complex II (CII)-dependent mitochondrial respiration and found a significant increase in the net active respiration supported by CI and the maximal uncoupled respiration in platelets harvested after CPB compared to those isolated pre-CPB. At variance, the active coupled respiration and electron transfer capacity for CII were decreased. The relative contribution of the complex cardiac pathology and CPB to the impairment of CII-dependent respiration and/or a possible relation with patients’ outcome are worth further investigation in a pilot study.

Angiotensin 2 impairs vascular function by activation of reactive oxygen species (ROS) production and development of endothelial dysfunction. Metformin, the first-line therapeutic agent for type 2 diabetes mellitus, has vascular protective properties, beyond its glucose lowering effects. The aim of the present study was to in-vestigate the interaction between metformin and angiotensin 2 in human internal mammary arteries harvested from patients with coronary heart disease undergoing revascularization procedure, by evaluation of vascular function, reactive oxygen species (ROS) production and the gene expression of nitric oxide (NO) synthases (endothelial – eNOS, neuronal – nNOS and inducible – iNOS). To this aim, vascular samples were incubated with angiotensin 2 (Ang2, 12 h) with/without metformin (Metf, 10 μM) and used for ROS measurement (FOX assay), vascular reactivity in organ bath (contractility to phenylephrine, relaxation to acetylcholine, con-tractility to NG-nitro-L-arginine methyl ester/L-NAME) and RT-PCT studies. Acute incubation of the vascular rings with Ang2 im-paired vascular reactivity (increase contractility, decrease relax-ation), increased ROS production, supressed eNOS/nNOS and in-creased iNOS mRNA expression. Ex vivo incubation with metfor-min at a clinically relevant concentration reversed all these ef-fects. These data suggest that Metformin might be useful in allevi-ating endothelial dysfunction by improving the endothelial-de-pendent relaxation and mitigating oxidative stress in clinical set-ting associated with cardiovascular disease regardless the pres-ence of impaired glucose metabolism.

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