Calcaterra, Ilenia Lorenza (2022) Changes in markers of atherosclerosis and multi-omic approach in patients with familial hypercholesterolemia treated with PCSK9 inhibitors. [Tesi di dottorato]

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Abstract

Background. PCSK9 inhibitors (PCSK9i) demonstrated efficacy in cholesterol reduction and in the prevention of cardiovascular events. We evaluated changes on lipid profile, lipid sub-fractions (sd-LDL and Lp(a)), subclinical atherosclerosis (assessed by FMD and carotid stiffness) and to explore potential pleiotropic effects of PCSK9i using an untargeted multi-omic approach before and at different time points, following treatment with the PCSK9i (evolocumab). Methods: Patients with FH starting a treatment with PCSK9i were included. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp(a)), small dense LDL (assessed by LDL score), 11-dehydro-thromboxane (11-TXB2), 8-iso-prostaglandin-2alpha (8-iso-PGF2α), flow-mediated dilation (FMD), reactive hyperaemia index (RHI), carotid stiffness and untargeted lipidomic and metabolomic analyses were evaluated before starting treatment and after 12 weeks of treatment. Results: Twenty-five subjects were enrolled (52% males, mean age 51.5 years). At 12-week assessment, the median reduction was 38% for TC, 52% for LDL-C, 7% for Lp(a) and 46% for LDL score. In parallel, 11-TXB2 and 8-iso-PGF2α were reduced of 18% and 17%, respectively. FMD changed from 4.78% ± 2.27 at baseline to 10.6% ± 5.89 (p < 0.001) at 12 weeks, with RHI changing from 2.37 ± 1.23 to 3.76 ± 1.36 (p < 0.001). Carotid stiffness changed from 8.8 (IQR: 7.0-10.4) m/sec to 6.6 (IQR: 5.4-7.5) m/sec, corresponding to a change of 21.4% (p < 0.001), with a significant increase in carotid distensibility (from 12.1, IQR: 8.73-19.3 kPA−1 × 10−3 at T0 to 21.8, IQR: 16.6-31.8 kPA−1 × 10−3 at T12w) corresponding to a median change of 62.8% (p < 0.001). Change in LDL score was an independent predictor of changes in FMD (β = -0.846, p = 0.015), carotid stiffness (β = 0.429, p = 0.041), and in 8-iso-PGF2α (β = 0.778, p = 0.012). At 12-week treatment, five polyunsaturated diacyl PC, accounting for 38.6 to 49.2 % of total PC at baseline, two ether/vinyl ether forms; seven SM, five CER and glucosyl/galactosyl-ceramide (HEX-CER) were reduced, as was the unsaturation index of HEX-CER and lactosyl—CER (LAC-CER). Although non quantitative modification was observed in phosphatidylethanolamine (PE) during treatment with PCSK9i, shorter and more saturated fatty acyl chains were documented. After peak validation and correction, after 12-week PCSK9i treatment as compared to baseline, we observed an increment of creatine (p-value = 0,041), indole (p-value = 0,045) and indoleacrylic acid (p-value= 0,045) concentrations. Conversely, a significant decrease in choline (p-value = 0,045) and phosphatidylcholine (p-value <0.01) together with the reduction of platelet activating factor (p-value = 0,041) was observed. Conclusions: Small dense LDL reduction is related to changes in oxidation markers, endothelial function and carotid stiffness in patients with FH treated with Evolocumab. Depletion of several phospholipid classes occurs in plasma of FH patients during treatment with the PCSK9i. The mechanism underlying these changes likely involves the de novo synthesis of SM and CER through the activation of the key enzyme sphingomyelin synthase by oxidized LDL and argues for a multifaceted system leading to vascular improvement in users of PCSK9i. Taking advantage of untargeted metabolomic, we first provide evidence of a concomitant reduction of inflammation and platelet activation metabolites in FH patients receiving a 12-week treatment with PCSK9i.

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