Randomized controlled trials will be needed to test the hypothesis that lowering Lp(a) or OxPL in patients with elevated levels truly slows down AS progression rates and ultimately improves clinical outcomes. had increased progression of valvular computed tomography calcium score (n?=?51; 309 AU/12 months [interquartile range: 142 to 483 AU/12 months] vs. 93 AU/12 months [interquartile range: 56 to 296 AU/12 months; p?=?0.015), faster hemodynamic progression on echocardiography (n?=?129; 0.23 0.20?m/s/12 months vs. 0.14 0.20?m/s/12 months] p?=?0.019), and increased risk for aortic valve replacement and death (n?=?145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p?=?0.014), compared with lower tertiles. Comparable results were noted with OxPL-apoB. In?vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against?OxPL. Conclusions In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis. test was performed, as (R)-UT-155 appropriate. To assess differences in categorical data across Lp(a) and OxPL tertiles, a chi-square test was performed. In multiple regression analysis, dependent variables were 18F-NaF uptake, aortic valve calcium score, and progression of peak aortic jet velocity. Independent variables included the baseline peak aortic jet velocity, baseline aortic valve calcium Rabbit Polyclonal to GPR150 score, Lp(a) and OxPL-apoB tertiles, and the traditional cardiovascular risk factor variables (age, sex, body mass index, history of cardiovascular disease, smoking status, diabetes mellitus, hypertension, and plasma creatinine). Following sensitivity analyses, baseline low-density lipoprotein cholesterol was not included in the multiple regression analysis (Online Table 2). Kaplan-Meier curves of time-to-event data were compared with the use of the log-rank test. Cox proportional hazards models were used to calculate hazard ratios by Lp(a) and OxPL-apoB tertiles. Unpaired Students and the major osteoblastic transcription factors and expression 2.1-fold (p?=?0.009), expression 3.2-fold (p?=?0.048) and expression 2.2-fold (p?=?0.020), compared with osteogenic medium only. Importantly, pre-incubation of Lp(a) with the E06 monoclonal antibody against OxPL markedly attenuated these Lp(a)-mediated osteogenic differentiation effects (Figures?5A to 5C). Open in a separate window Physique?5 Lp(a) Induces Osteogenic Differentiation in VICs (A to C) VICs in osteogenic media only conditions were used as the baseline comparator, while addition of TGF- served as a positive calcification control. One week of exposure to Lp(a) (100?mg/dl) induced gene expression of the inflammatory mediator and osteoblastic regulators and and expression. These transcriptional effects diminished with 17KLBS10, again supporting an important role for?OxPL (R)-UT-155 in mediating Lp(a)-induced VIC calcification (Figures?5D to 5F). In addition, when?assessing cell morphology, 17K-WT induced an activated rhomboid shape, suggesting VIC activation or phenotype transformation. In contrast, VICs exposed to 17KLBS10 demonstrated a spindle-shaped morphology, corresponding to (R)-UT-155 a quiescent state (Figures?5G and 5H). Discussion In this multimodality imaging study, we present the novel finding that increased Lp(a) and OxPL-apoB levels in elderly patients with advanced AS are associated with increased valvular calcification activity using 18F-NaF PET and confirmed faster rates of disease progression using both CT calcium scoring and echocardiography (Central Illustration). This translated into an increased incidence of AVR and death. In?vitro studies demonstrated that these observations appear to be driven by the pro-osteogenic effects of Lp(a) on VICs, mediated through its OxPL content, which could be alleviated with the E06 antibody that binds to and inactivates OxPL. Collectively, these data suggest that Lp(a) and its associated OxPL are important therapeutic targets in AS. Clinical trials are now warranted investigating whether novel Lp(a) lowering compounds or therapeutic antibodies targeting OxPL are effective in slowing disease progression in aortic stenosis. Open in a separate windows Central Illustration Lp(a) and OxPL Drive Disease Progression by Aggravating Calcification in Aortic?Stenosis?Patients Aortic stenosis patients with elevated levels of Lp(a) and OxPL-apoB demonstrate increased calcification activity in the valve as measured by 18F-NaF PET, compared with patients with low levels of Lp(a) and OxPL-apoB. During follow-up, this resulted in faster progression of CT calcium score and faster hemodynamic progression as measured by echocardiography. Ultimately, these patients have an increased risk of aortic valve replacement and death..