Biomechanical basis of intramyocardial hydrogel injection treatment for ischemic cardiomyopathy [snRNA-seq]

Adverse mechanical cues promote pathological remodeling of ischemic left ventricle, which leads to heart failure and mortality in ischemic cardiomyopathy (ICM) patients. Intramyocardial injection of hydrogels reduces the mechanical stress in left ventricular (LV) wall, thus preserves cardiac function and geometry. The therapeutic concept has been tested in clinical trials and presented exciting potential. However, the theory of intramyocardial hydrogel injection still needs to be improved as the molecular biological connection between the mechanical effect and therapeutic outcomes is weak, and it is difficult to clearly separate the contribution of hydrogel mechanical support from physiological reaction to hydrogel chemistry and combinational surgical procedures in previous clinical translation studies. In this study, we transendocardially injected alginate hydrogel via a percutaneous coronary intervention in 10 ICM patients with end-stage heart failure. Thirty days after injection, cardiac function was improved, and LV size was reduced. Stress in the myocardium decreased as evaluated by finite element analysis. Similar mechanical and functional effects by hydrogel injections were observed in rat myocardial infarction (MI) model. Bulk and single-cell RNA sequencing revealed restoration in transcription levels of mechanosensing, cardiac contraction genes and other important pathways, which was mainly attributed to changes in cardiomyocytes. Such effects were not observed in rats receiving diluted hydrogel, confirming that mechanical effect instead of material chemistry is the main contributor. The resemblance in transcriptomic profile and the effect of hydrogel injection on mechanical stress and remodeling of LV wall between ICM patients and diseased rats indicated the applicability of the major mechanistic conclusions in rat model to human.不良机械刺激可促进缺血左心室的病理性重构，进而引发缺血性心肌病（ischemic cardiomyopathy, ICM）患者的心力衰竭与死亡。心肌内注射水凝胶可降低左心室（left ventricular, LV）壁的机械应力，从而维持心脏功能与心室几何形态。该治疗理念已在临床试验中得到验证，展现出可观的应用前景。然而，由于机械效应与治疗结局之间的分子生物学关联较弱，且既往临床转化研究难以明确区分水凝胶机械支撑的作用、水凝胶化学特性引发的生理反应与联合手术操作的贡献，心肌内注射水凝胶的相关理论仍有待完善。本研究中，我们通过经皮冠状动脉介入术，对10例终末期心力衰竭的缺血性心肌病患者行经心内膜海藻酸盐水凝胶注射。注射后30天，患者心脏功能得到改善，左心室体积缩小；通过有限元分析（finite element analysis）评估可见心肌应力水平降低。在大鼠心肌梗死（myocardial infarction, MI）模型中，水凝胶注射也展现出相似的机械与功能效应。整体RNA测序（bulk RNA sequencing）与单细胞RNA测序（single-cell RNA sequencing）结果显示，机械感知、心脏收缩相关基因及其他关键通路的转录水平得以恢复，该效应主要由心肌细胞的变化介导。在注射稀释水凝胶的大鼠中未观察到此类效应，证实核心贡献因素为机械效应而非材料化学特性。缺血性心肌病患者与患病大鼠在转录组特征，以及水凝胶注射对左心室壁机械应力与重构的效应方面具有相似性，这表明大鼠模型中得到的主要机制结论可推广至人类。