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. Overall design: The rats were subjected to left anterior descending (LAD) coronary artery ligation (MI) along with Sham controls (Sham), and soft hydrogel (MI-soft) and stiff hydrogel (MI-stiff) treatment respectively, followed by heart tissue collection 28 days post MI to mimic the MI/R injury in AMI patients.The heart infarct zones (MI, MI-soft, MI-stiff and Sham) were isolated to single-nucleus transcriptome analysis. Collected nuclei for each sample were loaded onto 10X Chrominum platform. We obtained 69,608 cells and 20,748 genes. Five major cell types were identified, which included cardiomyocytes (CMs), endothelial cells (ECs), fibroblasts (FBs), macrophages (MACs) and smooth muscle cells (SMCs).