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A change of heart: new roles for cilia in cardiac development and disease

Abstract

Although cardiac abnormalities have been observed in a growing class of human disorders caused by defective primary cilia, the function of cilia in the heart remains an underexplored area. The primary function of cilia in the heart was long thought to be restricted to left−right axis patterning during embryogenesis. However, new findings have revealed broad roles for cilia in congenital heart disease, valvulogenesis, myocardial fibrosis and regeneration, and mechanosensation. In this Review, we describe advances in our understanding of the mechanisms by which cilia function contributes to cardiac left−right axis development and discuss the latest findings that highlight a broader role for cilia in cardiac development. Specifically, we examine the growing line of evidence connecting cilia function to the pathogenesis of congenital heart disease. Furthermore, we also highlight research from the past 10 years demonstrating the role of cilia function in common cardiac valve disorders, including mitral valve prolapse and aortic valve disease, and describe findings that implicate cardiac cilia in mechanosensation potentially linking haemodynamic and contractile forces with genetic regulation of cardiac development and function. Finally, given the presence of cilia on cardiac fibroblasts, we also explore the potential role of cilia in fibrotic growth and summarize the evidence implicating cardiac cilia in heart regeneration.

Key points

  • Cilia are antenna-like organelles that extend from most eukaryotic cells to obtain and interpret information from the extracellular environment; impaired ciliary signalling has been linked with congenital heart disease.

  • Intraciliary calcium signalling in the embryonic left–right organizer initiates vertebrate left–right patterning; abnormal left–right asymmetry is associated with major congenital heart disease, especially in heterotaxy syndrome.

  • Impaired cilia function and signalling are associated with heterotaxy, congenital heart disease, mitral valve prolapse and numerous other cilia-related disorders with cardiac abnormalities.

  • Primary cilia have a role in heart development beyond establishing left–right asymmetry.

  • Endocardial primary cilia might translate mechanical signals to gene expression during heart valve development.

  • Fibroblast cilia have been implicated in the regulation of cardiac regeneration.

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Fig. 1: Diversity of ciliary structure.
Fig. 2: Signalling pathways involved in heart development and organs involved in ciliopathies.
Fig. 3: Model for intraciliary calcium signalling in left–right patterning.
Fig. 4: Cilia defects and left–right patterning impairment leading to heterotaxy and congenital heart disease.
Fig. 5: Cilia-related genes linked to human congenital heart disease.
Fig. 6: Spatiotemporal distribution of primary cilia during valve development.
Fig. 7: Primary cilia as endocardial mechanosensors.

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Glossary

Cilia

Membrane-bound, microtubule-based, antenna-like sensory organelles that project from the surface of most animal cells to coordinate numerous signalling pathways during development and in tissue homeostasis.

Congenital heart disease

(CHD). A disease characterized by a structural abnormality of the heart that is not an acquired condition.

Left–right organizer

(LRO). Evolutionarily conserved embryonic ciliated organ of laterality in which breaking of left–right asymmetry occurs.

Heterotaxy

(HTX). Any arrangement of the organs across the left–right axis differing from situs solitus and situs inversus.

Atrioventricular septal defects

(AVSDs). Conditions characterized by improper atrial and ventricular septa and adjoining valve development.

Transposition of the great arteries

(TGA). A congenital heart defect characterized by a switch in the position of the pulmonary artery and the aorta.

Endocardial cushion

(ECC). A small pocket of cardiac jelly between the endocardial lining and the myocardium in the atrioventricular canal and outflow tract.

Atrioventricular canal

(AVC). The channel connecting the developing atrium and ventricles in embryonic development.

Outflow tract

(OFT). The channel connecting the developing ventricles and dorsal aorta in embryonic development.

Endothelial-to-mesenchymal transition

(EndoMT). The differentiation of endothelial cells to mesenchyme during cardiac cushion development.

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Djenoune, L., Berg, K., Brueckner, M. et al. A change of heart: new roles for cilia in cardiac development and disease. Nat Rev Cardiol 19, 211–227 (2022). https://doi.org/10.1038/s41569-021-00635-z

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