A-231 A novel assay measuring leukocyte lipid uptake and storage for treatment optimization in dyslipidemia and cardiovascular risk assessment

Abstract Background Elevated blood cholesterol, especially in the form of low-density lipoprotein cholesterol (LDL-C) is causing atherosclerotic cardiovascular c disease, one of the most common causes of death worldwide. Despite the availability of several treatment options to lower LDL-C, up to 80 % of high-risk patients do not achieve LDL-C target goals. Precision medicine applications are absent in dyslipidemia care and lipid-lowering medication is selected by measuring LDL-C, prescribing medication, following patients over time and adjusting the medication if needed. Previously, we established a semi-automated analysis platform which provides insight into cellular disease mechanisms, underlying dyslipidemia and the action of lipid-lowering drugs by quantifying LDL uptake and lipid storage in human leukocytes. We demonstrated large interindividual variability in cellular disease mechanisms in familial hypercholesterolemia patients, which associated with achieved LDL-C levels for statin medication. The main objective of this study was to elucidate how alterations in leukocyte LDL-uptake and lipid storage associate with circulating LDL-C and different lipoprotein subclasses in statin users from the general population. Secondary goals were to examine if altered leukocyte readouts are associated with increased cardiovascular risk and to investigate the interrelationship of cellular and genetic risk scores. Methods Interindividual differences for outcomes of lipid-lowering therapy are well known. Alterations in cellular pathways may contribute to this phenomenon. We utilized a semi-automated analysis platform to quantify LDL uptake and lipid storage for 400 subjects of the FINRISK 2012 study, including 200 recipients of lipid-lowering therapy and 200 matched controls. Then, cellular readouts were integrated with drug reimbursement, cardiovascular events, blood lipid values, genomic and NMR metabolomic data for all subjects. Results From our leukocyte LDL uptake and lipid storage readouts we derived two scores: a lipid mobilization score which reflects how leukocytes handle lipid storage when exposed to lipid-rich and lipid-poor conditions, and a lipid-trafficking score, which combines the lipid mobilization score with leukocyte LDL uptake potential. Low lipid-trafficking scores associated with increased LDL-C for recipients of high-intensity statin medication and subjects with a low lipid-trafficking score were less likely to achieve LDL-C target goals with high-intensity statins. Moreover, high intensity statin recipients with a low lipid-trafficking score displayed accumulation of pro-atherogenic lipoproteins including small VLDL, IDL and LDL particles. Interestingly, high intensity statin recipients with a low lipid mobilization or lipid trafficking score displayed an increased likelihood of experiencing a cardiovascular event. Our results suggest that individuals with altered leukocyte LDL uptake and lipid storage display increased residual cardiovascular risk, which is associated with an unfavorable lipoprotein profile, and quantification of cellular lipid trafficking can aid in treatment selection and risk assessment in dyslipidemia. Conclusion Our results indicate that systematic insight into cellular disease mechanisms derived from human leukocytes open up new opportunities for CVD risk assessment and optimization of treatment selection with precision medicine applications which go beyond traditional approaches utilizing blood lipid tests.