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Calcific aortic valve disease: mechanisms, prevention and treatment

Nature Reviews Cardiology volume 20, pages 546–559 (2023)Cite this article

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Abstract

Calcific aortic valve disease (CAVD) is the most common disorder affecting heart valves and is characterized by thickening, fibrosis and mineralization of the aortic valve leaflets. Analyses of surgically explanted aortic valve leaflets have shown that dystrophic mineralization and osteogenic transition of valve interstitial cells co-occur with neovascularization, microhaemorrhage and abnormal production of extracellular matrix. Age and congenital bicuspid aortic valve morphology are important and unalterable risk factors for CAVD, whereas additional risk is conferred by elevated blood pressure and plasma lipoprotein(a) levels and the presence of obesity and diabetes mellitus, which are modifiable factors. Genetic and molecular studies have identified that the NOTCH, WNT–β-catenin and myocardin signalling pathways are involved in the control and commitment of valvular cells to a fibrocalcific lineage. Complex interactions between valve endothelial and interstitial cells and immune cells promote the remodelling of aortic valve leaflets and the development of CAVD. Although no medical therapy is effective for reducing or preventing the progression of CAVD, studies have started to identify actionable targets.

Key points

  • Risk factors for calcific aortic valve disease (CAVD) include age, male sex, genetics, hypertension, smoking, diabetes mellitus, obesity, high plasma lipoprotein(a) levels and bicuspid aortic valve.

  • Genetic studies are revealing the polygenic architecture of CAVD, and the risk loci identified so far have emphasized the importance of lipids and cell signalling related to fibrosis, mineralization and inflammation in its pathogenesis.

  • Alterations to the haemostatic system, including the function of platelets, are associated with CAVD.

  • Evidence suggests that decreasing the plasma levels of lipids such as lipoprotein(a) might be most effective for preventing the onset of aortic valve mineralization.

  • Advances in data science together with multimodal tissue-based and single-cell genomic datasets will be key for future research into CAVD.

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Fig. 1: Structural organization of tricuspid and bicuspid aortic valves.
Fig. 2: Molecular pathways involved in mineralization in valve interstitial cells.
Fig. 3: Pathways and mechanisms in CAVD.

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Article 16 August 2019

Peter Libby, Julie E. Buring, … Eldrin F. Lewis

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Acknowledgements

The authors are supported by grants from the Canadian Institutes of Health Research to P.M. (FRN148778, FRN159697) and Y.B. (PJT-159641) and the Quebec Heart and Lung Institute Fund. Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. P.M. is the recipient of the Joseph C. Edwards Foundation granted to Université Laval.

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  1. These authors contributed equally: Louis-Hippolyte Minvielle Moncla, Mewen Briend.

Authors and Affiliations

  1. Laboratory Pathobiology of Cardiovascular Diseases, Quebec Heart and Lung Institute, Laval University, Quebec, QC, Canada

    Louis-Hippolyte Minvielle Moncla, Mewen Briend & Patrick Mathieu

  2. Department of Molecular Medicine, Laval University, Quebec, QC, Canada

    Yohan Bossé

  3. Department of Surgery, Laval University, Quebec, QC, Canada

    Patrick Mathieu

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L.-H.M.M., M.B. and P.M. researched data for the article, and all the authors discussed its content. L.-H.M.M., M.B. and P.M. wrote the manuscript, and all the authors reviewed/edited it before submission.

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Glossary

Allelic imbalance

Uneven expression of the two alleles of a gene.

Aortic valve stenosis

(AVS). Calcific aortic valve disease is a general term indicating that the aortic valve is thickened and mineralized; obstruction to the blood flow with an increased transaortic gradient is referred to as aortic valve stenosis.

Bicuspid aortic valves

Valves with two cusps instead of three; this congenital abnormality is present in 1–2% of the general population, is associated with other cardiovascular conditions (aortopathy) and syndromes (Turner syndrome and Loeys–Dietz syndrome), and is a risk factor for CAVD.

Dosage compensation

A process that balances the expression of genes between the sexes; in females (XX), inactivation of one X chromosome is a compensatory mechanism to match the level of gene expression in males (XY).

Ectonucleotidases

A group of secreted enzymes from different families that metabolize nucleotides and modulate purinergic signalling.

Endocardial-to-mesenchymal transition

An embryological process whereby cells from the endocardial cushion progressively acquire gene markers of mesenchymal cells.

Genome-wide association study

(GWAS). An observational study measuring associations between whole-genome common single-nucleotide polymorphisms and continuous or dichotomous outcomes (traits or disorders).

Heritability

The proportion of the variance in a trait that is explained by genetic variation within a population.

Homotypic interactions

Binding interactions involving two identical domains located on two different proteins.

Long non-coding RNA

(lncRNA). RNA molecules longer than 200 nucleotides that are not translated into protein; lncRNAs are often polyadenylated and involved in gene regulation.

Matricellular proteins

Secreted proteins that are not considered to be structural matrix molecules, but which modulate biological functions.

Mendelian randomization

A technique that uses gene variants as instrumental variables to infer causal association; Mendelian randomization assumes that instrumental variables are associated with the exposure and outcomes without independent pathways (horizontal pleiotropy).

NLRP3 inflammasome

A multimer complex that senses various danger signals and activates caspase 1; this process leads to the activation and secretion of IL-1β and IL-18.

Non-synonymous variant

A gene variant located in the coding part of a gene (exon) that substitutes an amino acid and changes the sequence of the protein.

Oscillatory blood flow

A blood flow pattern characterized by cyclical forward and reverse flow of varying intensities.

Quantitative trait loci

Correlation between loci markers, such as single-nucleotide polymorphisms, and quantitative traits, such as gene expression, protein levels or other molecular traits.

Resolvins

ω-3 Fatty acid-derived mediators that act locally to limit inflammation and to restore cell functions.

Shear stress

The frictional force applied to the vascular wall or valve and which is proportional to the blood flow velocity.

Single-nucleotide polymorphism

The most common form of germline genetic variation, consisting of the substitution of a single nucleotide at a specific location in the genome.

Super-enhancers

A collection of nearby distant cis-regulatory elements (enhancers) that are associated with cell fate and are often enriched in gene variants associated with complex traits and disorders.

Transcription factor

A protein that binds to a specific sequence of DNA and controls the transcriptional process; transcription factors can promote or repress transcription and are involved in cell fate and lineage commitment.

X chromosome inactivation

A process by which one of the X chromosomes in female organisms is inactivated to limit allelic imbalance between males (with one X chromosome) and females (with two X chromosomes).

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Moncla, LH.M., Briend, M., Bossé, Y. et al. Calcific aortic valve disease: mechanisms, prevention and treatment. Nat Rev Cardiol 20, 546–559 (2023). https://doi.org/10.1038/s41569-023-00845-7

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