br Conclusion and future perspectives LDL cholesterol loweri

Conclusion and future perspectives LDL cholesterol-lowering therapy is essential for cardiovascular risk reduction. On the background of a high inter-personal variation of cholesterol synthesis and cholesterol N6-Methyl-ATP synthesis the efficacy of cholesterol lowering, both, with statins and with ezetimibe exhibits a wide variation. Bempedoic acid, which reduces cholesterol synthesis through inhibition of adenosine triphosphate citrate lyase, an enzyme upstream from 3-hydroxy-3-methylglutaryl-coenzyme A, may provide an oral therapeutic option complementary to ezetimibe in statin-intolerant patients who require additional LDL-C lowering (Ruscica, Banach, Sahebkar, Corsini, & Sirtori, 2019). The determination of markers of cholesterol metabolism offers the unique opportunity to get a more detailed understanding of the individual patient. Therefore, future clinicians will need to “get personal” in their counseling and prescription of cholesterol-lowering agents to become more effective in the prevention of cardiovascular disease progression. Future approaches call for “individualized” concepts in lipidology. To establish these concepts, individual differences in cholesterol metabolism and their effects on different cholesterol-lowering strategies deserve increased scrutiny and investigation.
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Acknowledgments
Introduction Autosomal dominant hypercholesterolemias (ADH) are characterized by high levels of low-density lipoprotein (LDL) cholesterol, familial presentation and high risk of premature cardiovascular disease [1]. Most ADH have familial hypercholesterolemia (FH) due to mutations in the LDLR gene that encodes for the LDL receptor [2]. Approximately 2–15% of ADH subjects have familial defective apolipoprotein B-100 (FDB) due to mutations in the LDL receptor-binding domain coding region of the APOB gene, which encodes for apolipoprotein B-100 [3], or mutations in proprotein convertase subtilisin/kexin type 9 gene (PCSK9), a protein involved in the LDL receptor recycling [4]. Recently, a mutation in APOE (p.Leu167del) has been also associated with ADH [5], [6]. Patients with mutations in these genes present an indistinguishable phenotype and are now included in the FH definition [2]. The genetic cause and pathogenic mechanism of approximately 20–40% of ADH, named in short as non-FH ADH, are unknown [7], [8], and probably they are a heterogeneous group of diseases including some severe polygenic hypercholesterolemias [9]. Cholesterol concentration in plasma depends on the amount of cholesterol from the diet and its intestinal absorption, on de novo synthesis, and on its biliary excretion [10]. Previous studies have reported increased intestinal cholesterol absorption in non-FH ADH subjects that may partially explain plasma hypercholesterolemia in these subjects [11], [12]. However, no familial cosegregation studies have been performed to study the linkage between hyper-absorption and high LDL cholesterol in non-FH ADH families. Normal serum contains small but detectable amounts of non-cholesterol sterols, including plant sterols, also named phytosterols, and cholestanol, and their ratios to cholesterol are accepted surrogate markers for the efficiency of cholesterol intestinal absorption [13], [14]. Efficiency of cholesterol intestinal absorption is a partly inherited phenomenon. Heredity of cholesterol absorption has been demonstrated in siblings of hypercholesterolemic probands with low and high serum cholestanol to cholesterol ratio [15].
Materials and methods
Results The main clinical and biochemical characteristics of the 54 non-FH ADH probands are presented in Table 1. Probands were mostly healthy women (65%) with high total cholesterol and LDL cholesterol and normal triglycerides as expected due to inclusion and exclusion criteria. The concentration of the non-cholesterol sterols is represented by ratio to total cholesterol determined by HPLC-MS/MS.