DOI: 10.1161/circ.148.suppl_1.13045 ISSN: 0009-7322

Abstract 13045: Myofibroblasts Revert to an Inactive Phenotype During Regression of Heart Failure

Chao Yang, Yuxing Chen, Lianlian Zhu, Lan Zhang, Xiangmin Kong, Qiyu Chen, Xue Liu, Yue Wu, Xinyang Hu, Wei Zhu, Jian'an Wang
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: The therapy of left ventricular mechanical unloading, such as transcatheter aortic valve replacement(TAVR)and left ventricular assist devices(LVAD)has significantly improved prognosis for patients with heart failure. However, the detailed cellular and/or molecular mechanisms of recovery of cardiac function remain unknown.

Objective: We aimed to build a cellular atlas of the heart that experienced stress and de-stress process, with a focus on myofibroblasts, specifically its cell fate of differentiation and function.

Methods: We conducted single-cell and ATAC sequencing on non-myocardial cells from mouse heart samples of pressure overload-induced heart failure and recovery, using TAC (transverse aortic arch constriction)/deTAC (with suture for the constriction removed 2 weeks after TAC) model to identify the dynamic changes. Lineage tracing technique was also used to gain further insight into cell fate and reciprocal interactions. Macrophage subgroup was cleared using various approaches to investigate the cross-talk between myofibroblast and macrophage.

Results: We generated a TAC/deTAC mouse model which can faithfully simulate a reversal process of functioning for the heart that underwent a pressure overload stress. Multi-omics sequencing reveals the genetic changes and transcriptional regulation of cell populations at different stages. Among the different cell types, significant changes in the gene expression pattern were observed in fibroblasts. Aided by myofibroblast lineage tracing, flow cytometry examinations suggested that remaining in a quiescent state rather than showing a decrease in its number appeared as the main fate of myofibroblasts. Surprisingly, however, simultaneous pressure unloading and macrophage clearance resulted in a significant reduction in the number of myofibroblasts.

Conclusions: With a reliable TAC/deTAC mouse model, our multi-omics data revealed dynamic changes in cell populations of the heart that underwent pressure overload followed by unloading, our data demonstrated a quiescent state rather than a reduction in number was the major fate for the activated myofibroblasts for which macrophages were involved. These findings provide a theoretical basis for further treatment.

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