Lipoprotein(a) Pegged as Aortic Stenosis Biomarker, Culprit, and Treatment Target

May 03, 2019

A study that combined several forms of imaging to track aortic stenosis (AS) progression in elderly patients and its relation to lipoprotein biomarkers has concluded that those biomarkers don't just reflect worsening AS, they help drive it.

Their suppression in the laboratory seemed to inhibit a cellular process involved in the progression of valvular calcification in AS, further suggesting that either or both of the biomarkers may be worthy treatment targets, conclude the study's authors, led by Kang H. Zheng, MD, Academic Medical Center, Amsterdam.

The group says their study, published in the May 7 issue of the Journal of the American College of Cardiology, is the first to use PET, CT, and echocardiography to track aortic valve calcification with respect to levels of lipoprotein(a), or Lp(a), and associated oxidized phospholipids (OxPL).

Patients with both AS and elevated Lp(a) levels "had increased disease activity in their valves, demonstrated faster aortic stenosis progression, and moved more quickly toward aortic valve replacement," senior author Marc R. Dweck, University of Edinburgh, United Kingdom, told | Medscape Cardiology.

"Our in vitro work suggests this is because Lp(a) promotes calcification via the actions of OxPL."

Taken together, he said, "our data suggest Lp(a) and OxPL are key therapeutic targets in patients with elevated levels and aortic stenosis."

The association between AS and elevations in Lp(a) is well known. Although there's evidence from multiple directions that it's also a player in the disease process, a causative role hasn't been firmly established.

"At the moment we don't have any medical therapies capable of slowing aortic stenosis progression, so the development of such treatments is a major unmet clinical need," Dweck said.

Statins don't lower Lp(a) levels, nor do they affect AS progression; there is some evidence that Lp(a) levels decline on treatment with the PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen).

Potentially, Dweck said, either Lp(a) or OxPL could be treatment targets. "This is exciting because we now have powerful emerging treatments that can target both Lp(a) or OxPL." Whether they pan out as treatments for AS, however, will require randomized trials.

The 145 patients in the analysis with advanced AS — averaging 70 years of age and two-thirds of whom were men — were taken from two prospective studies looking at AS using multiple imaging modalities and followed for a median of 5 years.

They were the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) trial and the Ring of Fire study.

Patients who were in the top tertile for Lp(a) concentration (>35 mg/dL) showed significantly greater aortic valvular calcification activity, an indicator of AS progression, by 18F-sodium fluoride (NaF) PET imaging compared with those in Lp(a) tertiles 1 or 2 (≤35 mg/dL).

With zones of ongoing calcification preferentially incorporating 18F-NaF, patients in tertile 3 showed a tissue-to-background ratio for the tracer of 2.16, compared with 1.97 for lower tertiles (= .043).

Being in Lp(a) tertile 3 was a predictor of 18F-NaF uptake (P = .002) independent of baseline calcium scores and traditional cardiovascular (CV) risk factors, the group reported.

Results were similar by OxPL-level tertile: the 18F-NaF tissue-to-background ratio was 2.15 for subjects in tertile 3 (>2.8 nanomolar) and 1.98 (P = .047) for those in tertiles 1 or 2 (≤2.8 nanomolar). OxPL was also a significant independent predictor of 18F-NaF uptake (P = .016).

Aortic valve calcium scores by CT, aortic valve function by echocardiography, and clinical outcomes in the cohort all supported the PET findings.

With the same adjustment for calcium scores and CV risk factors, tertile 3 for both Lp(a) (= .003) and OxPL (P = .005) was an independent predictor of annualized aortic valve CT calcium-score progression.

After adjustment for baseline peak aortic jet velocity and traditional CV risk factors, tertile 3 significantly predicted progression of echocardiographic peak aortic jet velocity over time, compared with tertiles 1 and 2, for Lp(a) concentration (P = .034). The predictive power for OxPL tertile 3 fell short of significance (P = .054).

Clinically, the hazard ratio (HR) for the composite of all-cause mortality or aortic valve replacement was significantly increased for tertile 3 vs tertiles 1 and 2 at 1.87 (95% CI, 1.13 - 3.08; P = .014) for Lp(a) and 1.83 (95% CI, 1.11 - 3.02; P = .024) for OxPL.

The in vitro part of the study looked at the effects of both Lp(a) and OxPL on valvular interstitial cells. Lp(a) induced osteogenic differentiation of those cells, a process that underlies valvular calcification, and which was mediated by OxPL, the group observed.

Introduction of an anti-OxPL monoclonal antibody inhibited that process.

"This innovative study is the first to deploy a direct measurement of aortic valve tissue calcifying activity — namely, 18F-NaF PET and CT — to correlate plasma Lp(a)-OxPL levels with ongoing calcific aortic valve disease mineralization in patients," writes Dwight A. Towler, MD, PhD, UT Southwestern Medical Center, Dallas, in an accompanying editorial.

That the various metrics of disease progression were tracked over time "further highlights the effect of the robust, mechanism-based experimental design," he writes.

"Moreover, the accompanying in vitro data provide functional evidence that neutralizing Lp(a) activity and/or associated OxPL metabolism can limit the osteogenic mineralization responses of the valve interstitial cell."

Zheng had no disclosures. Dweck had no relevant disclosures. The report includes disclosures for the other authors. "Towler has been approached as a consultant for new osteoporosis medication, but has not yet received any payments or remuneration," the editorial states.

J Am Coll Cardiol. 2019;73:2150-2162, 2163-2165. Full text, Editorial

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