Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3795_Библиотеки_им_академика_М_И_Перельмана-1

outcomes in patients with elevated Lp(a) levels affected by CAVD are in progress and the results are not available yet. Nicotinic acid (niacin) is known to have beneficial effects on very low-density lipoprotein (VLDL), LDL, and to significantly lower plasma Lp(a) concentrations [51], probably due to an inhibitory effect on LPA transcription [52]. In addition, findings from several studies showed an association of niacin therapy with increment of HDL levels [53]. Of note, there is a relationship between low HDL levels and fast CAVD progression [54]. Indeed, apolipoprotein A–I mimetic peptide, that has been shown to elevate transiently circulating HDL cholesterol in mice and rabbits, prevented mineralization of aortic valve and even pro- moted AS regression [55, 56]. Interestingly, infusion of recombinant apolipoprotein A–I Milano in rabbits had positive effects on morphology and histopathology of stenotic aortic valve, with significant reduction of valve thickening, inflammation, and calcification [57]. Recently, a large clinical trial investigated the effect of statin therapy alone or in combination with extended-release niacin (ERN) in patients with CVD but without high levels of LDL at baseline [58, 59]. In this study, a favourable effect of ERN on apolipoproteins and in particular on Lp(a) was shown. However, these positive changes did not influence CV events occurrence. The pilot randomized trial Early Aortic Valve Lipoprotein (a) Lowering (EAVaLL) (NCT02109614) was designed to evaluate whether lowering Lp(a) at an early stage of CAVD could affect the disease progression. A cohort of 238 participants with elevated Lp(a) and AVSc or mild AS is currently been enrolled and randomized to receive ERN or placebo for 2 years. The primary outcome of the study is the assessment of calcium score progression evaluated by cardiac computed tomography. The secondary outcome is the evaluation of mean change in Lp(a) levels between treatment arms, while other outcomes include: a) rates of CAVD progression by echocardiography; b) drug compliance; and c) side effects and adverse events. The results of this important study will help us to clarify our knowledge about the pharmacological effect of niacin on CAVD progression. Nevertheless, it is important to take into account that niacin has several side effects, such as gastrointestinal and musculoskeletal disorders or even increased risk of diabetes [53]. In light of these recent trials and studies, we believe that in the future guidelines patients affected by AS should be screened for Lp(a) levels and should be treated if high Lp(a) is found.

radically lowering LDL (up to 70%), are also able to lower plasma Lp(a) (up to 30%) [63]. The Lp (a) reduction obtained by inhibiting PCSK9 was surprising since Lp(a) has not been considered to be catabolized through LDL receptors [64]. Both antibodies are associated with a significant reduction in CV events [45]. The FOURIER trial, published on March 2017, is a randomized, double-blind, placebo-controlled, multinational clinical trial in which 27′564 patients, receiving statin therapy, underwent randomization to receive subcutaneous injections of evolocumab (140 mg; 2 weeks or 420 mg; 1 month) or placebo. Overall, LDL levels were reduced by 59% from baseline compared to placebo and this therapy resulted in a significant reduction in the risk of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina by 15% and the risk of cardiovascular death, myocardial infarction, or stroke by 20% [65]. In a cohort of Danish individuals (n = 103′083) a LOF mutation of PCSK9 (R46 L) was associated not only with lower levels of LDL but also with lower levels of Lp(a) and with reduced risk of AS and myocardial infarction. These results suggest that individuals with AS could benefit from a therapy with PCSK9 inhibitors [66]. Interestingly, in a small cross-sectional study, PCSK9 levels correlated with the presence but not with the severity of CAVD [67]. Therefore, a randomized control trial (NCT03051360) is now underway to investigate the effects of PCSK9 inhibitors vs placebo on AS progression (Table 3). Final data collection and estimated study completion date are expected by early 2020. Currently, on debate is in which way PCSK9 influences Lp(a) levels. It has been shown a correlation between chronic inflammatory infiltrates, osteochondrogenic metaplasia, and neovascularization of aortic valve [68, 69]. A dense inflammatory infiltrate within the valve tissue was associated with the remodeling process and the peak transaortic gradient [68]. Thanks to fluorodeoxyglucose–positron emission tomography/computed tomography, a method that provides information about valvular metabolic activity, it has been shown that early manifestation of aortic valve lesion (i.e., AVSc) was associated with inflammation [2]. Indeed, early and advanced aortic valve lesions are both characterized by the presence of inflammation [70]. Notably, inflammation induces PCSK9 overexpression that leads to increasing LDL levels as a result of an accelerated LDL receptor degradation [71, 72]. In addition, circulating PCSK9 positively correlated with C reactive protein (CRP) [73], and, at the same time, CRP was found in the fibrosa of stenotic aortic valve. Thus, the presence of CRP in AS might activate the classical complement system [74]. In summary, since PCSK9 seems directly linked to inflammation, PCSK9 inhibitors may have also therapeutic benefits in patients with early/asymptomatic manifestation of CAVD.