Bioactive lipids in plasma and atherogenic apoB-containing lipoproteins: Effects of statins and PCSK9 inhibitors and relevance to residual cardiovascular risk.
Source: PubMed, NCBI / U.S. National Library of Medicine
Despite major advances in lipid-lowering therapeutics, significant residual cardiovascular risk persists in dyslipidemic patients in primary and secondary prevention, even after optimization of LDL-cholesterol levels. All atherogenic apoB-containing lipoproteins, (VLDL and remnants, IDL, LDL and Lp(a)), exert deleterious effects on the arterial wall and atherosclerotic plaque, contributing to such risk. Mass spectrometric analyses have revealed that apoB-containing lipoproteins contain a diverse array of lipid classes (≥ 30); together with their constituent molecular species (> 1000), their lipidome is highly complex. The bioactivities of certain lipid classes may contribute to residual cardiovascular risk, such as sphingolipids and lysolipids; others, such as plasmalogens (alkenylphospholipids), may afford atheroprotection. Indeed, beyond eicosanoids, the majority of plasma lipid classes exhibit bioactivities. Mass spectrometric platforms lack harmonisation of reference plasmas and internal standards for quantitation however, limiting comparison of absolute plasma lipid concentrations. In common hyperlipidemias, major bioactive lipids such as free cholesterol, cholesteryl ester or triacylglycerol typically predominate; nonetheless, levels of other lipid classes (phosphatidylcholine, phosphatidylinositol, phosphatidylserine, alkyl and alkenylphospholipids, sphingomyelin, ceramide and lysophosphatidylcholine) can distinguish hypercholesterolemia, hypertriglyceridemia an
Abstract
Despite major advances in lipid-lowering therapeutics, significant residual cardiovascular risk persists in dyslipidemic patients in primary and secondary prevention, even after optimization of LDL-cholesterol levels. All atherogenic apoB-containing lipoproteins, (VLDL and remnants, IDL, LDL and Lp(a)), exert deleterious effects on the arterial wall and atherosclerotic plaque, contributing to such risk. Mass spectrometric analyses have revealed that apoB-containing lipoproteins contain a diverse array of lipid classes (≥ 30); together with their constituent molecular species (> 1000), their lipidome is highly complex. The bioactivities of certain lipid classes may contribute to residual cardiovascular risk, such as sphingolipids and lysolipids; others, such as plasmalogens (alkenylphospholipids), may afford atheroprotection. Indeed, beyond eicosanoids, the majority of plasma lipid classes exhibit bioactivities. Mass spectrometric platforms lack harmonisation of reference plasmas and internal standards for quantitation however, limiting comparison of absolute plasma lipid concentrations. In common hyperlipidemias, major bioactive lipids such as free cholesterol, cholesteryl ester or triacylglycerol typically predominate; nonetheless, levels of other lipid classes (phosphatidylcholine, phosphatidylinositol, phosphatidylserine, alkyl and alkenylphospholipids, sphingomyelin, ceramide and lysophosphatidylcholine) can distinguish hypercholesterolemia, hypertriglyceridemia and diabetic dyslipidemia. From a therapeutic standpoint, statin treatment efficaciously reduces levels of all plasma lipid classes in atherogenic dyslipidemias. Further, ratios of specific molecular species of phosphatidylinositol/phosphatidylcholine and of molecular species of ceramides post-statin may represent biomarkers of cardiovascular benefit in secondary prevention, independently of LDL-C. Importantly, PCSK9 inhibitor therapy in statin combination is distinguished from statin monotherapy by its more pronounced effect on plasma levels- and relative ratios- of specific ceramide species. These findings highlight the impact of PCSK9 inhibitors both on ceramide metabolism itself and the potential contribution of these bioactive sphingolipids to the residual CV risk typical of statin monotherapy.