Early Changes in the Plasma Lipidome of People at Very High Cardiovascular Risk: A New Approach to Assessing the Risk of Cardiovascular Changes

<b>Background/Objectives:</b> Cardiovascular disease (CVD) remains the leading cause of death worldwide and requires a deeper understanding of its pathogenesis for effective prevention and treatment. Familial hypercholesterolemia (FH), characterized by high levels of LDL cholesterol, is a significant risk factor for CVD. FH background remains unexplained despite advances in genetic testing. The aim was identification early changes in the plasma lipidome of individuals at high cardiovascular risk (HCVR) using liquid chromatography coupled with mass spectrometry. <b>Methods</b>: The lipidomic analysis examined over 400 compounds. Twenty individuals with suspected FH, very high cardiovascular risk (VHCVR), and undetectable mutations in the <i>LDLR</i>, <i>APOB</i>, or <i>PCSK9</i> genes were compared to control group in a qualitative-quantitative analysis. <b>Results</b>: Multivariate analyses revealed statistically significant alterations in glycerophospholipids (GC), with a notable increase in phosphatidylcholines ((O-36:0/16:0), OR (95% CI): 1.246 (1.042-1.490), <i>p</i> = 0.0157), phosphatidylethanolamines ((O-40:7/22:6), OR (95% CI): 1.119 (1.039-1.205), <i>p</i> = 0.0028), and phosphatidylglycerol ((40:8/20:4), OR (95% CI): 1.053 (1.008-1.101), <i>p</i> = 0.0219) only in patients with HCVR. These changes, particularly in major classes of GC, underscored their potential as biomarkers for early assessment of cardiovascular risk. Lipidomic profiling revealed associations between specific lipid species and the comorbidities of arterial hypertension, atherosclerosis, and insulin resistance, implicating their role in atherosclerotic cardiovascular disease (ASCVD). <b>Conclusions</b>: This study points early changes in the plasma lipidome in individuals at HCVR, underline potential biomarkers, therapeutic targets for ASCVD, and offer opportunities to improve ASCVD diagnosis, therapy, and risk management strategies through detailed personalized medical approach.