👤 Daiana Ibarretxe

Lipoprotein(a) (Lp(a)) is a proatherogenic particle that is considered an important cardiovascular risk modifier due to its association with atherosclerotic cardiovascular disease (ASCVD) as well as calcific aortic valve stenosis (CAVS). Data on the clinical burden associated with elevated lipoprotein(a) levels in patients at high and very high cardiovascular risk remain limited. We evaluated the prevalence of ASCVD and LDL-C target achievement in subjects with high and very high elevated Lp(a) levels referred to a lipid unit. In this retrospective study, 1755 subjects were evaluated; 265 with Lp(a) ≥240nmol/L were included. The population was divided into two groups: high Lp(a) (240-429nmol/L, n=216) and very high Lp(a) (≥430nmol/L, n=49). ASCVD prevalence was 58% in the very high group and 48% in the high group (p=0.23). Age and statin intensity were higher in the very high Lp(a) group. LDL-C target achievement was low in both groups: 20.0% and 25.4% of very high-risk patients reached <55mg/dL as well as 18.2% and 17.2% of high-risk patients reached <70mg/dL in very high and high Lp(a) groups, respectively. Subjects with elevated Lp(a) levels showed a high prevalence of ASCVD and low LDL-C target attainment despite high-intensity statin therapy. These findings support the need for Lp(a) screening and additional lipid-lowering strategies in high-risk patients. Show less

Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by the presence of 2 pathogenic variants in the LDLR, APOB, PCSK9, or LDLRAP1 genes, which cause very high levels of LDL-cholesterol and premature atherosclerotic cardiovascular disease (ASCVD). To analyze the current situation regarding diagnosis, cardiovascular disease, lipid-lowering treatment, and degree of control of lipids in patients with HoFH in the National Dyslipidemia Registry of the Spanish Atherosclerosis Society. Subjects with HoFH, confirmed by the presence of 2 pathogenic variants in the genes mentioned above, included in the registry from 2013 to June 2023 with an updated review were analyzed. Of 71 included subjects with HoFH, 40.8% were women, aged 52 [24-62] years, 57 adults and 13 children. The median follow-up was 7 [4-13] years. Age of diagnosis was 14 [2-26] years, with 10% of ASCVD at diagnosis and 27% of current ASCVD at 40.6 (13.4) years of age; 38% were on PCSK9 inhibitors, 9 patients on lomitapide, 9 on LDL apheresis, and 1 patient on evinacumab. Subjects with more than 4 therapies achieved >80% reduction in LDLc. In the last visit, the median LDLc was 139.3 [89.4-204.2] mg/dL. ASCVD was strongly associated with male sex and family history of ASCVD, relative risk 5.26 (1.53-18.10) and 2.53 (1.03-6.26), P < .05, respectively. Only 18% and 10% meet the recommended LDLc goal in primary and secondary prevention respectively. The current situation of HoFH in Spain is better than expected, with marked reductions in LDLc levels with new treatments. In this population, recommended LDLc goals are difficult to achieve despite maximum lipid-lowering therapy. ASCVD has been reduced and delayed by 2 decades. Show less

Preclinical studies suggest that a triglyceride (TG)-independent proinflammatory action of apolipoprotein C-III (apoCIII) exists. We aimed to investigate the relationship between circulating apoCIII levels and subclinical inflammation markers across different cohorts with distinctive inflammatory patterns: patients with metabolic disorders (MDs), patients with rheumatoid arthritis (RA), and controls. Specifically, we assessed the associations of apoCIII with acute inflammation biomarkers (e.g., high sensitivity C-reactive protein (hsCRP)) and novel systemic inflammation biomarkers (e.g., glycosylated proteins: Glyc-A, Glyc-B, Glyc-F), aiming to understand the role of apoCIII beyond its traditional function in TG metabolism. This cross-sectional study involved 1242 participants: 906 patients with MD (metabolic syndrome, type 2 diabetes (T2DM) and/or obesity), 192 patients with RA, and 144 controls. ApoCIII and hsCRP levels were measured via immunoturbidimetric assays, and glycosylated proteins were quantified via 1 H-NMR spectroscopy. Correlation and multivariate linear regression analyses were conducted. ApoCIII levels were significantly and positively associated with Glyc-A, Glyc-B, and Glyc-F levels across all cohorts. Most of these associations remained significant in the MD group after adjusting for TG levels. Conversely, negative associations were detected between apoCIII and hsCRP patients with MD and RA, which were maintained after including TG in the models. In patients with MD and RA, circulating apoCIII levels were positively associated with glycoproteins and negatively with hsCRP, in a TG-independent manner. Our results suggest that apoCIII is associated with the low-grade inflammatory profile represented by glycoproteins, independent of triglyceride levels. Additionally, we observed a negative association with hsCRP, which, while seemingly paradoxical, has been reported in previous studies. Show less

Despite the various therapeutic tools available, many patients do not achieve therapeutic goals, and cardiovascular diseases remain a significant cause of death in our setting. Furthermore, even in patients who manage to reduce their LDL-C levels to the recommended targets, cardiovascular events continue to occur. The therapeutic challenge and the persistent risk have led to active research into new drugs targeting novel therapeutic pathways in the field of lipoprotein metabolism disorders. The therapeutic approach involves new pharmacological mechanisms, ranging from small molecules and monoclonal antibodies to RNA interference, with inclisiran being the first drug approved for clinical use in the cardiovascular domain. In this review, we aim to provide a comprehensive overview of the new therapeutic targets and pharmacological mechanisms under development, as well as their potential clinical impact. Show less

While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL-triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by Show less

Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex. This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry. Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5). Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326₃₂₇insC; p.Tyr110Leufs*158). We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS. Show less

Apolipoprotein A5 gene (APOA5) variability explains part of the individual's predisposition to hypertriacylglycerolaemia (HTG). Such predisposition has an inherited component (polymorphisms) and an acquired component regulated by the environment (epigenetic modifications). We hypothesize that the integrated analysis of both components will improve our capacity to estimate APOA5 contribution to HTG. We followed a recruit-by-genotype strategy to study a population composed of 44 individuals with high cardiovascular disease risk selected as being carriers of at least one APOA5 SNP (-1131T>C and/or, S19W and/or 724C>G) compared against 34 individuals wild-type (WT) for these SNPs. DNA methylation patterns of three APOA5 regions [promoter, exon 2 and CpG island (CGI) in exon 3] were evaluated using pyrosequencing technology. Carriers of APOA5 SNPs had an average of 57.5% higher circulating triacylglycerol (TG) levels (P=0.039). APOA5 promoter and exon 3 were hypermethylated whereas exon 2 was hypomethylated. Exon 3 methylation positively correlated with TG concentration (r=0.359, P=0.003) and with a lipoprotein profile associated with atherogenic dyslipidaemia. The highest TG concentrations were found in carriers of at least one SNP and with a methylation percentage in exon 3 ≥82% (P=0.009). In conclusion, CGI methylation in exon 3 of APOA5 acts, in combination with -1131T>C, S19W and 724C>G polymorphisms, in the individual's predisposition to high circulating TG levels. This serves as an example that combined analysis of SNPs and methylation applied to a larger set of genes would improve our understanding of predisposition to HTG. Show less