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Lp(a)/OxPL Aggravate Calcification in Aortic Stenosis Patients
Study Questions:
Are lipoprotein (a) [Lp(a)] and oxidized phospholipids (OxPL) on apolipoprotein B-100 (OxPL-apoB) associated with disease activity/progression and clinical events in patients with aortic stenosis (AS), and what are potential mechanisms?
Methods:
In this translational study, the authors performed two sets of analyses: The first was a post hoc analysis of a pooled cohort of 145 patients with AS, examining whether plasma levels of Lp(a) and OxPL-apoB correlated with aortic calcification as measured by 18F sodium fluoride positron emission tomography (18F-NaF PET) at baseline, and whether levels predicted progression of AS as assessed by computed tomography calcium scores, change in peak transvalvular aortic velocity by echocardiogram, and composite clinical outcome of death and aortic valve replacement. The second set of analyses were from in vitro experiments examining the effects of exposing valvular interstitial cells to Lp(a).
Results:
In the clinical analyses, while there were no differences in baseline characteristics including calcium score and valve hemodynamics between patients with Lp(a) >35 mg/dl or OxPL >2.8 nmol/L and those with lower levels, there was evidence of increased calcification activity, as measured by 18F-NaF PET in the top Lp(a) tertile. At follow-up, patients in the top Lp(a) tertile also had more severe valvular calcification, higher peak gradients across the aortic valve, and were at higher risk of valve replacement or death. Similar results were noted in the OxPL group. In the in vitro experiments, exposure of valvular intersitial cells to Lp(a) induces expression of inflammatory markers like interleukin-6 and osteoblastic transcription factors (BMP2, RUNX2). Preincubation with a monoclonal antibody against OxPL markedly attenuated these effects.
Conclusions:
Elevated Lp(a) and OxPL-apoB levels are associated with valvular calcification and accelerated disease progression in patients with AS. Lp(a) and OxPL may be pathogenically involved and represent potential therapeutic targets to slow disease progression.
Perspective:
This multifaceted translational study is an excellent example of how combining clinical and basic sciences can lead to identification of novel therapeutic targets. The findings are exciting and novel, as there are currently no effective treatment strategies to slow the progression of AS. The enthusiasm, however, is dampened by limitations to the study: While the findings appear to be internally consistent, the sample size was small with inconsistent availability of data across imaging modalities. Moreover, the differences and effect sizes were small with wide confidence intervals. These findings will need to be replicated in a larger cohort allowing for more detailed analyses, prior to venturing into costly drug development and clinical trials.
Keywords: Aortic Valve Stenosis, Apolipoproteins B, Calcinosis, Diagnostic Imaging, Echocardiography, Heart Valve Diseases, Hemodynamics, Interleukin-6, Lipoproteins, Phospholipids, Positron-Emission Tomography, Sodium Fluoride, Tomography, X-Ray Computed
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