Biggs Rachel M, Zhang Yuhua, Silverman Daniel N, Baicu Catalin F, Van Laer An O, Wakefield Lauren, Bhatt Devki, Masline Stephanie, Neff Lily S, Kilic Arman, Witer Lucas J, Houston Brian A, Coeyman Samuel J, Richardson William J, Zile Michael R, Bradshaw Amy D
Division of Cardiology, Department of Medicine Medical University of South Carolina Charleston SC USA.
The Ralph H. Johnson Department of Veteran's Affairs Health Care System Charleston SC USA.
J Am Heart Assoc. 2025 Apr 15;14(8):e039747. doi: 10.1161/JAHA.124.039747. Epub 2025 Apr 10.
Myocardial fibrosis is prevalent in cardiomyopathies that result in heart failure with reduced ejection fraction. Heart failure with reduced ejection fraction treated with a left ventricular assist device (LVAD) yields hemodynamic unloading and may provide partial cardiomyocyte recovery, but contemporary studies reveal no consistent reductions in fibrosis. This study tested the hypothesis that, despite normalization of hemodynamic overload by LVAD, fibrosis and fibroblast activation persist resulting in sustained increases in myocardial stiffness.
Tissues from subjects with heart failure with reduced ejection fraction undergoing LVAD implantation (pre-LVAD), from transplanted hearts with LVAD (post-LVAD) or without cardiac pathology (control) were collected. Quantification of myocardial stiffness and collagen content revealed significant increases in pre-LVAD versus control that remained elevated in post-LVAD. Myocardial fibroblast populations increased in pre- and post-LVAD hearts versus control. Control, pre-LVAD, and post-LVAD fibroblasts were isolated and plated on substrates with mechanical stiffnesses reflective of normal (≈2 kPa) or fibrotic (≈8 kPa) myocardium. Quantification of collagen I and α-smooth muscle actin production demonstrated that control fibroblasts were responsive to substrate stiffness, whereas pre- and post-LVAD fibroblasts were unresponsive and exhibited no significant differences on either substrate. Bulk-RNA sequence analysis revealed changes in gene expression in pre-LVAD versus control fibroblasts including mechano-sensitive pathways that appear to be uncoupled, resulting in increased expression of genes implicated in proliferation, whereas mechano-sensing genes were decreased.
These data support that sustained cardiac hemodynamic overload leads to a phenotypic conversion in fibroblasts in which the capacity to detect changes in mechanical input is muted, thus contributing to retention of collagen content and stiffness in both pre- and post-LVAD hearts.
心肌纤维化在导致射血分数降低的心力衰竭的心肌病中普遍存在。使用左心室辅助装置（LVAD）治疗射血分数降低的心力衰竭可实现血流动力学卸载，并可能使部分心肌细胞恢复，但当代研究表明纤维化并无持续减轻。本研究检验了以下假设：尽管LVAD使血流动力学过载正常化，但纤维化和成纤维细胞激活持续存在，导致心肌僵硬度持续增加。
收集了接受LVAD植入的射血分数降低的心力衰竭患者（LVAD植入前）、移植的带有LVAD的心脏（LVAD植入后）或无心脏病变的对照者的组织。心肌僵硬度和胶原蛋白含量的定量分析显示，LVAD植入前与对照组相比显著增加，且在LVAD植入后仍保持升高。与对照组相比，LVAD植入前和植入后的心脏中成纤维细胞数量增加。分离出对照、LVAD植入前和植入后的成纤维细胞，并接种在具有反映正常（≈2kPa）或纤维化（≈8kPa）心肌机械僵硬度的基质上。I型胶原蛋白和α-平滑肌肌动蛋白产生的定量分析表明，对照组成纤维细胞对基质僵硬度有反应，而LVAD植入前和植入后的成纤维细胞无反应，且在两种基质上均无显著差异。批量RNA序列分析揭示了LVAD植入前与对照组成纤维细胞中基因表达的变化，包括机械敏感通路似乎解偶联，导致与增殖相关的基因表达增加，而机械传感基因减少。
这些数据支持持续的心脏血流动力学过载导致成纤维细胞发生表型转化，其中检测机械输入变化的能力减弱，从而导致LVAD植入前和植入后的心脏中胶原蛋白含量和僵硬度保持不变。
