Myocardial Fibrosis in Hypertrophic Cardiomyopathy: A Perspective from Fibroblasts

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and the leading cause of sudden cardiac death in young people. Mutations in genes that encode structural proteins of the cardiac sarcomere are the more frequent genetic cause of HCM. The disease is characterized by cardiomyocyte hypertrophy and myocardial fibrosis, which is defined as the excessive deposition of extracellular matrix proteins, mainly collagen I and III, in the myocardium. The development of fibrotic tissue in the heart adversely affects cardiac function. In this review, we discuss the latest evidence on how cardiac fibrosis is promoted, the role of cardiac fibroblasts, their interaction with cardiomyocytes, and their activation via the TGF-β pathway, the primary intracellular signalling pathway regulating extracellular matrix turnover. Finally, we summarize new findings on profibrotic genes as well as genetic and non-genetic factors involved in the pathophysiology of HCM.

Keywords: TGF-β; cardiac fibroblast; hypertrophic cardiomyopathy; myocardial fibrosis; myofibroblasts.

Figure 1

TGF-β signalling in cardiac fibroblasts. TGF-β is activated by proteolytic cleavage from the latent complex. Binding to the heterodimeric TGF-β receptor (TβR-I/TβR-II) activates profibrotic signalling cascades via canonical or non-canonical signalling pathways. The canonical pathway involves the phosphorylation of Smad2 and Smad3 and the association with Samd4. The complex translocates to the nucleus and regulates the transcription of profibrotic genes. Non-canonical TGF-β signalling comprises several different pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), and Rho GTPases (Rho) pathways, which also alter the expression of fibrotic genes. Created with BioRender.com.