P4485The number of lipoprotein(a) kringle IV-type 2 repeats is associated with the osteogenic profile of aortic valvular interstitial cells induced by plasma from patients with calcific aortic stenosis
Bibliographic record
Abstract
Abstract Background Considerable progresses have been made in the invasive treatment of calcific aortic stenosis (AS), but there is still no pharmacological treatment available because the exact mechanism leading to the initiation of valvular calcification remains unknown. An increasing number of evidences, including large-scale genetic studies, have linked Lipoprotein(a) (Lp(a)) to AS but its pathogenic role in the osteoblastic transition of valvular interstitial cells (VIC) has remained undeciphered. Objective We sought to study the mechanistic link between the transition of VICs towards an osteoblastic phenotype leading to intraleaflet calcium deposition and the type of Lp(a) isoform, defined by the number of kringle IV-type 2 (KIV 2) repeats, in the plasma of patients with AS compared with healthy controls. Methods VICs isolated from healthy aortic valves were cultured in the presence of plasma samples deriving from 100 patients with severe AS included in the prospective cohort GENERAC and 50 matched control patients exempt from any aortic valve disease. We evaluated the number of Lp(a) KIV 2 repeats of each plasma preparation by liquid chromatography-mass spectrometry. The phenotypic changes of VICs towards an osteoblastic phenotype were assessed by immunofluorescence microscopy (osteocalcin expression) and Alizarin red staining (calcium deposition). Results Incubation of VICs with the plasma of AS patients triggered their transformation towards an osteoblastic phenotype, evidenced by the production of osteocalcin, and calcium deposition. There was no association between the plasma levels of Lp(a) and the extent of calcium deposition in the study population. However, a negative and significant correlation was found between calcium deposition and the number of KIV-2 repeats in the Lp(a) of the different plasma preparations (r=−0.20, p=0.038). A direct, causal role of Lp(a) isoforms containing a low number of KIV-2 repeats (5 to 6) in the transition of VICs towards an osteoblastic phenotype was supported by experiments performed with preparations of these isoforms, isolated from the plasma of blood donors. Conclusion A low number of KIV–2 repeats in plasma Lp(a) triggers the acquisition of an osteoblastic phenotype by VICs. The isoform, rather than the concentration of Lp(a) may play a pathogenic role in AS. Determining the number of KIV-2 repeats in the Lp(a) of patients may allow to identify subgroups of patients with an increased risk of developing AS. Acknowledgement/Funding ANR-16-RHUS-0003_STOP-AS. PHRC National 2005 and 2010, and PHRC regional 2007.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".