👤 Paul M M Weers

Lipoprotein(a) [Lp(a)] is a known independent risk factor for cardiovascular disease, yet awareness and management remain limited. The psychosocial implications of elevated Lp(a)-levels have been poorly characterized. To compare cardiovascular outcomes and cardiovascular risk factor (CVRF) modification in individuals with normal vs. elevated Lp(a) levels, and to assess the impact of individualized prevention recommendations. For the first time, the individual psychological stress caused by Lp(a) is being surveyed. The ELITE study is a prospective, interventional cohort study conducted in north-western Germany. Participants were regularly assessed for CVRFs, including Lp(a), hypertension, dyslipidemia, diabetes mellitus, weight, nicotine - as well as lipoprotein (a), physical activity, dietary habits, depression and stress. They received written, personalized prevention recommendations. Follow-up averaged 4.4 years. Two groups were analyzed: Group 1 (Gr1, n=3,241) with normal Lp(a), and Group 2 (Gr2, n=841) with elevated Lp(a ≥75 nmol/l). Gr2 (mean Lp(a) 154.8 nmol/l) and Gr1 (mean Lp(a) 16.4 nmol/l) were comparable in age (~53 years) and sex distribution (~49% female). Most participants with elevated Lp(a) were previously unaware of their levels; 30% were referred to specialists, and ~40% reported concern or anxiety. Combined cardiovascular endpoints (CHD, stroke, heart failure, PAD, carotid stenosis, AF) occurred significantly more often in Gr2 (p<0.001), despite similar CVRF profiles, except for higher baseline LDL-C in Gr2 (p<0.001). Hypertension (61%) and physical inactivity (57%) were the most prevalent CVRFs. Personalized prevention measures led to significant improvements in blood pressure, LDL-C, smoking, physical activity, and weight in both groups. Lipid-lowering therapy improved markedly in Gr2 (12% to 23%). Elevated Lp(a) is associated with a significantly higher rate of cardiovascular events, independent of traditional CVRFs. This confirms a causal role of Lp(a) in CV morbidity. Personalized written prevention recommendations improved CVRFs across both groups, though further optimization is needed. Notably, elevated Lp(a) also imposes a psychosocial burden, underlining the need for enhanced education, counseling, and clinical pathways. Show less

Previous studies of recombinant full-length human apolipoprotein A-V (apoA-V) provided evidence of the presence of two independently folded structural domains. Computer-assisted sequence analysis and limited proteolysis studies identified an N-terminal fragment as a candidate for one of the domains. C-Terminal truncation variants in this size range, apoA-V(1-146) and apoA-V(1-169), were expressed in Escherichia coli and isolated. Unlike full-length apoA-V or apoA-V(1-169), apoA-V(1-146) was soluble in neutral-pH buffer in the absence of lipid. Sedimentation equilibrium analysis yielded a weight-average molecular weight of 18811, indicating apoA-V(1-146) exists as a monomer in solution. Guanidine HCl denaturation experiments at pH 3.0 yielded a one-step native to unfolded transition that corresponds directly with the more stable component of the two-stage denaturation profile exhibited by full-length apoA-V. On the other hand, denaturation experiments conducted at pH 7.0 revealed a less stable structure. In a manner similar to that of known helix bundle apolipoproteins, apoA-V(1-146) induced a relatively small enhancement in 8-anilino-1-naphthalenesulfonic acid fluorescence intensity. Quenching studies with single-Trp apoA-V(1-146) variants revealed that a unique site predicted to reside on the nonpolar face of an amphipathic alpha-helix was protected from quenching by KI. Taken together, the data suggest the 146 N-terminal residues of human apoA-V adopt a helix bundle molecular architecture in the absence of lipid and, thus, likely exist as an independently folded structural domain within the context of the intact protein. Show less

Human apolipoprotein A-V (apoA-V) is a potent modulator of plasma triacylglycerol (TG) levels. To probe different regions of this 343-amino-acid protein, four single Trp apoA-V variants were prepared. The variant with a Trp at position 325, distal to the tetraproline sequence at residues 293-296, displayed an 11-nm blue shift in wavelength of maximum fluorescence emission upon lipid association. To evaluate the structural and functional role of this C-terminal segment, a truncated apoA-V comprising amino acids 1-292 was generated. Far UV circular dichroism spectra of full-length apoA-V and apoA-V-(1-292) were similar, with approximately 50% alpha-helix content. In guanidine HCl denaturation experiments, both full-length and truncated apoA-V yielded biphasic profiles consistent with the presence of two structural domains. The denaturation profile of the lower stability component (but not the higher stability component) was affected by truncation. Truncated apoA-V displayed an attenuated ability to solubilize l-alpha-dimyristoylphosphatidylcholine phospholipid vesicles compared with full-length apoA-V, whereas a peptide corresponding to the deleted C-terminal segment displayed markedly enhanced kinetics. The data support the concept that the C-terminal region is not required for apoA-V to adopt a folded protein structure, yet functions to modulate apoA-V lipid-binding activity; therefore, this concept may be relevant to the mechanism whereby apoA-V influences plasma TG levels. Show less