NMR‐based lipoprotein analysis for patients with severe hypercholesterolemia undergoing lipoprotein apheresis or PCSK9‐inhibitor therapy (NAPALI‐Study)

Abstract

Taking into account the discordance between low‐density lipoprotein cholesterol (LDL‐C) and LDL particle (LDL‐P) number, cardiovascular risk more closely correlates with LDL‐P in patients. The aim of our study was to evaluate the number of lipid particles in patients with severe hypercholesterolemia treated with different lipid‐lowering regimens. Four groups of patients differing with respect to lipid‐lowering therapy were recruited from hypercholesterolemic outpatients and lipoprotein apheresis (LA) facilities, and were treated with statins alone (group A), with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) (group B), with statins and LA (group C), or with statins, PCSK9i, and LA (group D). Cholesterol, triglycerides, LDL‐C, high‐density lipoprotein cholesterol (HDL‐C), LDL‐P number and size, HDL‐P number and size were determined using nuclear magnetic resonance spectroscopy. The lowest LDL‐P number was achieved at the end of LA sessions in combination with statins or in combination with statins and a monoclonal PCSK9i (median; 25th and 75th percentile) (group C: 244 nmoL/L: 237, 244, P < 0.05; group D: 244 nmoL/L: 99, 307, P < 0.05). Comparing LDL‐P number at the start of LA (group C: 978 nmoL/L: 728, 1404; group D: 954 nmoL/L: 677, 1521) to the other patient groups (groups A and B), the lowest LDL‐P number was measured in patients treated with PCSK9i and a statin (group B): LDL‐P (762 nmoL/L: 604, 1043, P < 0.05), large LDL‐P (472 nmoL/L: 296, 574, P < 0.05), and small LDL‐P (342 nmoL/L: 152, 494, P < 0.05). Very low‐density lipoprotein and HDL particle sizes remained approximately the same in all groups. LA in combination with statins or in combination with statins and PCSK9i most reduced LDL‐P numbers in hypercholesterolemic patients.

Treatment with PCSK9 inhibitors induces a more anti-atherogenic HDL lipid profile in patients at high cardiovascular risk

“…The present study confirmed that patients at high cardiovascular risk treated for four weeks with PCSK9-I displayed a major decrease in the levels of total cholesterol and atherogenic lipids, including LDL-C and non-HDL-C, as well as apoB. A moderate but significant increase in HDL-C and apoA-I was also observed, which is an effect of PCSK9-I that has been previously reported in a number of clinical trials, albeit with some discrepancies [14,15,[28][29][30][31][32]. Although the level of HDL-C has been repeatedly inversely related to cardiovascular risk in epidemiological studies, a single measurement of HDL-C does not necessarily reflect the functionality of HDL particles and their pleiotropic atheroprotective properties.…”

“…To date, only four studies have analyzed the effects of PCSK9-I therapy on HDL particle profiles measured by NMR, with one study reporting no change [14], while the others found a moderate increase Journal Pre-proof in the total HDL-P level of approximately 10% [15][16][17]. However, the aforementioned studies were performed in patients from randomized controlled trials and were mostly restricted to analysis of the total HDL-P concentration.…”

Serum level of HDL particles are independently associated with long-term prognosis in patients with coronary artery disease: The GENES study

“…Also, no classification for HDL subclasses analysed by NMR has been yet approved for routine purpose. For instance, the analytical method developed by LipoScience (now LabCorp, Raleigh, NC) grouped HDL particles into 3 subclasses from small (S-HDL-P, 7.3-8.2 nm), medium (M-HDL-P, 8.2-9.4 nm) to large (L-HDL-P, 9.4-14 nm) with small and medium-sized HDL particles being sometimes grouped (MS-HDL-P, 7.3-9.4 nm), while the AXINON lipoFIT-S100 system (Numares AG, Regensburg, Germany) used in the present study grouped HDL subclasses into small (SHDL-P, 7.3-8.7 nm) and large (LHDL-P, 8.8-13 nm) 11,12 . In this latest classification, it is worth mentioning that the estimated diameter ranges for SHDL-P and LHDL-P were similar to those for HDL 3c+3b+3a (7.2-7.8 nm; 7.8-8.2 nm; 8.2-8.8 nm) and HDL 2a+2b (8.8-9.7 nm; 9.7-12.9 nm), respectively, as isolated from plasma by density gradient ultracentrifugation and analyzed by electrophoresis on a nondenaturing gel 13,14 .…”

“…HDL measurement by nuclear Magnetic Resonance (nMR) spectroscopy. HDL particle concentration and size were measured by NMR spectroscopy using the AXINON lipoFIT-S100 test system (Numares AG, Regensburg, Germany) as previously described 11,12,23 . Serum samples for NMR spectroscopy were stored at −80 °C and kept unthawed until the day of NMR measurements.…”

NMR-Based Lipid Metabolite Profiles to Predict Outcomes in Patients Undergoing Interventional Therapy for a Hepatocellular Carcinoma (HCC): A Substudy of the SORAMIC Trial

“…Although mass spectrometry-based approaches can resolve a higher number of metabolites than NMR spectroscopy, clear advantages of the NMR technique include the non-destructive character of the analysis, simple sample processing and high analytical reproducibility. A standardized NMR platform was shown to be a powerful analytical tool for an in-depth lipoprotein analysis in various contexts [ 9 , 10 , 11 , 12 , 13 ]. Recently, a metabolomic analysis using the same technology and AI-based approaches allowed the identification of constellations of urinary and blood metabolites as novel biomarkers for a non-invasive assessment of a renal allograft rejection [ 14 , 15 ] and the precise estimation of a kidney function [ 16 ], respectively.…”