Single-cell transcriptomics uncovers immune remodeling in heart failure complicated by myocarditis
G Li, C Lian, C Zhao, R Wang, M Liu, X Zheng, T Shi, Y Li, R Wang, Y Yan, Y ZhangAbstract
Background
Heart failure (HF) is a leading cause of morbidity and mortality, marked by progressive loss of contractile reserve and cardiac remodeling. Myocarditis accelerates HF progression and promotes cardiomyopathy. However, the cellular and signaling mechanisms linking inflammation to cardiomyocyte dysfunction in HF with myocarditis are not well understood. A mechanistic understanding is critical for identifying therapeutic pathways and improving risk stratification.
Purpose
To characterize the cellular landscape and communication networks in cardiomyopathy complicated by myocarditis, focusing on immune–metabolic interactions driving cardiomyocyte injury, stress adaptation, and remodeling.
Methods
Single-cell RNA sequencing (scRNA-seq) of left ventricular tissue was conducted across three groups: Control (n=5), cardiomyopathy without myocarditis (CM−MYO, n=10), and cardiomyopathy with myocarditis (CM+MYO, n=4). Cell populations were annotated using UMAP-based clustering. Cell–cell communication was analyzed with CellChat to assess immune-cardiomyocyte signaling. Ultrastructural changes were validated by transmission electron microscopy (TEM), and an experimental autoimmune myocarditis (EAM) mouse model is being used for validation.
Results
In CM+MYO, cardiomyocyte proportions decreased by 9.7% and 8.7% compared to Control and CM−MYO, with immune cells increasing by 5.0% and 9.8%, respectively. CellChat revealed T cells and macrophages as key contributors to immune-cardiomyocyte communication. Although T-cell subclusters showed immune-activation gene upregulation, no CM+MYO-specific signaling pathway linking T cells to cardiomyocytes was found. A lipid-associated macrophage (LAM) population enriched in CM+MYO exhibited mitochondrial remodeling, oxidative stress, and immune infiltration pathways, suggesting a role in cardiomyocyte dysfunction and tissue injury. CM+MYO-specific cardiomyocyte subpopulations, such as Contractile–Stress Responsive cardiomyocytes, showed an "injury–stress–remodeling" phenotype with autophagy and cytoskeletal remodeling pathways. LAM-cardiomyocyte communication indicated enhanced NAMPT signaling, which, along with high OLR1 expression in LAMs, suggests macrophage polarization to a lipid-associated state, amplifying metabolic stress in cardiomyocytes and leading to maladaptive remodeling. TEM confirmed macrophage lipid phagocytosis and cardiomyocyte injury, including sarcomere disarray and mitochondrial abnormalities.
Conclusions
HF with myocarditis is associated with immune–cardiomyocyte remodeling, marked by lipid-associated macrophages and enhanced NAMPT signaling, leading to a stress-responsive cardiomyocyte phenotype. The OLR1–NAMPT–INSR axis may offer therapeutic targets for HF with myocarditis.