👤 Ernestina Marianna De Francesco

Familial hypercholesterolemia (FH) is characterized by elevated LDL-C and an increased risk of premature cardiovascular events. Inclisiran is a small interfering RNA that inhibits hepatic PCSK9 synthesis and promotes LDL-C clearance by enhancing LDLR expression on hepatocytes. This study aimed to evaluate the efficacy of six-months add-on inclisiran on lipid profile and PWV in FH; furthermore, we investigated the association between LDL-C reduction and PWV variation. This prospective observational study involved 78 genetically confirmed FH subjects with an LDL-C off-target despite high-intensity statins plus ezetimibe. All subjects obtained biochemical analysis and PWV evaluation at baseline and after six months add-on inclisiran. After six months add-on inclisiran, 41 % of subjects achieved LDL-C targets. Significant reductions of LDL-C (-41.5 %, p < 0.001), ApoB (-33.7 %, p < 0.01), Non-HDL-C (-35.9 %, p < 0.001), and Lp(a) (-18 %, p < 0.01) were observed, while PWV improved by 14.4 % (p < 0.001). In a secondary analysis, the Primary prevention group showed a higher prevalence of subjects on LDL-C target than the Secondary prevention group (59 % vs 23.1 %, p < 0.001). Both groups exhibited significant improvements of lipid profile and PWV (Δ - 14.1 %, p < 0.01 and Δ - 14.6 %, p < 0.001, respectively). Linear regression showed a significant association between ΔPWV and ΔLDL-C in the whole study population as well as in the Primary and Secondary prevention groups (p for all <0.001). Inclisiran significantly improved lipid profile and PWV in FH subjects. ΔPWV was significantly associated with ΔLDL-C. Show less

Familial hypercholesterolemia (FH) is characterized by lifelong elevated LDL-C levels and increased cardiovascular risk. PCSK9 inhibitors (PCSK9i) reduce LDL-C and Lp(a), however, the effect of dual lipid reduction on mechanical vascular function remains unclear. The aim of this study was to evaluate the efficacy of PCSK9i in reducing LDL-C and Lp(a) and to assess the relationship between the dual lipid reduction and the mechanical vascular profile improvement in FH subjects. This prospective observational study included 301 genetically confirmed FH subjects treated with PCSK9i added to high-intensity statins and ezetimibe. Biochemical and PWV measurements were performed at baseline and after six months. Subjects were stratified into four groups based on median values of ΔLDL-C and ΔLp(a). After six months of add-on PCSK9i, 44.9% of FH subjects achieved their LDL-C targets. Reductions were observed in LDL-C (− 49.8%, Dual lipid reduction with PCSK9i was associated with a pronounced mechanical vascular profile improvement in FH subjects; however, an intensive Lp(a) reduction may be needed to achieve a greater mechanical vascular benefit. Show less

Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻⁸) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹⁷), MC4R (P = 4.41 × 10⁻¹⁷), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻⁹), GNPDA2 (P = 1.11 × 10⁻⁸) and POMC (P = 4.94 × 10⁻⁸) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻⁵ after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages. Show less