Convergent plasma and valve-tissue omics link vitamin B12 bioavailability to aortic stenosis
V Myasoedova, F M Mattio, V Valerio, V Rusconi, F Bertolini, A Bonomi, I Massaiu, P PoggioAbstract
Background
Mild-to-moderate vitamin B12 deficiency can raise homocysteine levels, promoting atherosclerosis and aortic valve degeneration, increasing cardiovascular risk.
Purpose
Whether altered B12 metabolism contributes to the development or progression of aortic stenosis (AS) remains uncertain.
Methods
We prospectively enrolled 150 individuals at our cardiology centre [controls (CTRL), aortic valve sclerosis (AVSc), and AS]. Circulating plasma proteins were profiled with the OLINK CVD2 panel, and AS-associated proteins were validated by ELISA. Differential expression data from previously generated RNA-seq of aortic valve tissue were used to explore convergent molecular pathways. Finally, an independent external cohort of patients undergoing cardiac surgery (n=168) was examined to clinically assess B12-related alterations in AS.
Results
Protein profiling identified 11 analytes significantly different across CTRL, AVSc, and AS groups (ANOVA p<0.05). ELISA validation confirmed downregulation of gastric intrinsic factor (GIF), the key protein required for intestinal vitamin B12 absorption into the bloodstream, in AS patients versus CTRL (p=0.0016). RNA-seq analysis showed reduced expression of CD320, the receptor needed for cellular B12 uptake, in AS tissue compared to CTRL (p=0.0073). In the external cohort, patients with severe AS displayed lower circulating B12 levels compared to AVSc and CTRL (p-for-trend=0.014; Bonferroni adj p=0.039 vs CTRL).
Conclusion
Integrating circulating proteomics, valve-tissue transcriptomics, and independent clinical validation, our findings point to impaired vitamin B12 transport and availability in AS. Mild B12 deficiency may represent an under-recognized and potentially modifiable contributor to AS progression, offering new opportunities for risk stratification and targeted intervention.