Author + information
- Rômulo Dias Novaes, PhD∗ ( )()
- ↵∗Federal University of Alfenas, Institute of Biomedical Sciences, Department of Structural Biology, Gabriel Monteiro da Silva, 714, 37130-001, Alfenas, Minas Gerais, Brazil
From a prospective study involving 64 patients with end-stage heart failure, Farris et al. (1) proposed a model, based on the interaction of macrophages and fibroblasts, to explain similar cardiac fibrosis before and after the placement of a left ventricular assist device (LVAD). According to the authors, before LVAD, the high collagen expression by fibroblasts is balanced by collagen degradation by M1 macrophage proteinases, whereas, after LVAD, expression of M2 pro-fibrotic and fibroblast collagen genes decreases together with expression of proteinases by M1 macrophages, resulting in fibrosis persistence. By focusing on stromal cells, the authors bring a new perspective to the understanding of the pathogenesis of myocardial fibrosis.
To broaden the understanding of cardiac remodeling in heart failure, it would be relevant to contextualize histopathological findings in relation to normal cardiac structure. From the microscopic images, no extensive inflammation or fibrosis was observed. Thus, the extent of myocardial remodeling and how much collagen content differs from normal hearts is poorly understood. Because fibroblast-extracellular matrix interactions regulate collagen synthesis (2), low-grade disturbances in cell-matrix interaction could be insufficient to activate signaling pathways associated with collagenogenesis or collagenolysis. Thus, assuming that fibrosis is already established, it is unclear how far myocardial collagen would regress until a morphofunctional dynamic equilibrium is established.
At the molecular level, it is also unclear as to what extent gene expression is upregulated in loaded or downregulated in unloaded LVAD hearts compared with basal expression. Thus, valid questions are: 1) Was pro-fibrotic genetic programming really activated in the context investigated? or 2) Was inhibition of gene transcription an isolated consequence of LVAD? Furthermore, collagen synthesis is not an unequivocal consequence of gene expression in loaded hearts, especially considering that post-transcriptional mechanisms are equally relevant for terminal protein synthesis and destination (3,4). Emblematic examples are chaperones and ubiquitin-proteasome systems, which are deregulated in end-stage heart failure, and determine failure of protein quality control, especially when combined with intense gene transcription (5). This aspect was reinforced by the similarity in collagen content in loaded and LVAD unloaded hearts, indicating that gene expression in the loaded group may not fully explain fibrosis. Thus, the similarity in collagen content could be more dependent on post-transcriptional metabolism than a direct role of macrophage phenotype on collagen dynamics. However, inhibition of matrix metalloprotease synthesis by the cardiac fibroblasts should also not be disregarded as an explanation for fibrosis persistence in LVAD unloaded hearts.
Please note: Dr. Dias Novaes has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
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