A novel etiology of Left Ventricular Non-Compaction

Left ventricular non-compaction (LVNC) is a heterogenous cardiac disorder characterized by excessive trabeculations and deep trabecular recesses in the left ventricle, with clinical outcomes that range from asymptomatic to heart failure, arrhythmias, and sudden cardiac death¹. LVNC is considered as a primary genetic cardiomyopathy according to the American Heart Association², but it is still “unclassified” in the most recent Statement of the European Society of Cardiology³, illustrating the need for better understanding of the origins of this disease. Its prevalence is growing and it is considered as the third most common cardiomyopathy.

LVNC is thought to arise from an arrest of normal compaction of the extensive mesh of trabeculae present in the embryonic ventricles during development⁴. However, despite its importance in the formation of an efficient ventricular myocardium, ventricular compaction is poorly understood. Recent findings have shown that a non-compaction phenotype arises when proliferation of compact, but not trabecular, cardiomyocytes was inhibited⁵. Moreover, Kristy Red-Horse’s lab has shown that endothelial-cardiomyocyte crosstalk is also required, suggesting that, beside cardiomyocytes, other cell types are involved in the etiology of this cardiomyopathy⁶.

In this paper published in European Heart Journal, Rhee et al. identified secreted molecules from endothelial or endocardial cells that drive cardiomyocyte proliferation and maturation⁷. They used single-cell RNA sequencing to characterize and compare the molecular signatures of individual cell types from control and non-compacted fetal mouse hearts. They identified a specific cluster of proliferating endocardial cells in non-compacted hearts. Regarding cardiomyocytes, they found differential molecular signatures between control and mutant cells, with an increase in genes involved in glycolysis, hypoxia and fatty acid metabolism. They also found that known genes associated with LVNC in human are found dysregulated in cell types other than cardiomyocytes, demonstrating the importance of the cross talk between these different cell types during ventricular development. Most importantly, they found Col15a1 to be downregulated in mutant and a rescue experiment shows that adding Col15a1 to primary culture of non-compacted cardiomyocytes improves their proliferation capacity. Moreover, they identified upregulation of four secreted factors from non-compacted endocardium that inhibit cardiomyocyte proliferation and stimulate maturation. Finally, they showed that blocking coronary angiogenesis results in a non-compaction phenotype.

This study shows the importance of vascular-derived factors, or angiocrines, that can influence cardiomyocytes behavior by modulating their proliferation and maturation - key cellular processes in ventricular compaction. The findings point to a novel etiology of LVNC, by which dysregulation of paracrine signaling from endothelial cells can reduce cardiomyocyte proliferation and induce a non-compaction phenotype.