Deciphering the cardiac neuron landscape in heart failure patients.

A cardiac neuron landscape comprising 11,026 neuronal cells was generated from integrated single-nucleus RNA sequencing data.

• Data were integrated from published snRNA-seq datasets from 75 patients with heart failure and 45 healthy donors.
• Ten distinct neuronal cell subsets were identified, differing in abundances, compositions, and biological functions in the heart.
• The integration approach allowed comprehensive characterization of molecular and functional diversity across neuronal cell types.

N4-ALK neurons were significantly enriched in failing hearts relative to healthy controls.

• N4-ALK neurons represented one of the ten distinct neuronal cell subsets identified in the cardiac neuron landscape.
• Their abundance was specifically elevated in heart failure patients compared to the 45 healthy donors.
• The enrichment of N4-ALK neurons distinguished failing from non-failing cardiac tissue at the single-cell level.

The abundance of N4-ALK neurons was associated with the response to left ventricular assist device (LVAD) implantation.

• N4-ALK neuron abundance tracked with patient response to LVAD implantation, a mechanical cardiac support intervention.
• This association suggests N4-ALK neurons may play a functional role in cardiac remodeling or recovery in heart failure.
• The finding links a specific neuronal subset to a clinically relevant therapeutic outcome measure.

RXRG, a transcription factor highly expressed in neuronal cells, participated in the transcriptional regulatory network of N4-ALK neurons and showed a positive correlation with their marker gene expression.

• RXRG was identified as highly expressed specifically in cardiac neuronal cells.
• RXRG was found to participate in the transcriptional regulatory network governing N4-ALK neurons.
• A positive correlation was observed between RXRG expression and the expression of N4-ALK neuron marker genes.
• This positions RXRG as a potential transcriptional regulator of the N4-ALK neuronal subset in the failing heart.

The PTN-PTPRZ1 signaling axis mediated specific crosstalk between cardiac fibroblasts and N4-ALK neurons in heart failure.

• Cell-cell communication analysis identified the PTN-PTPRZ1 ligand-receptor axis as a specific interaction between cardiac fibroblasts and N4-ALK neurons.
• This crosstalk was identified specifically in the context of heart failure.
• The finding implicates fibroblast-neuron signaling as a component of the pathological cardiac remodeling process in heart failure.

N4-ALK-related features were used to develop an optimized prediction model for identifying individuals with heart failure.

• A prediction model was constructed using features derived from N4-ALK neuron gene signatures.
• The model was described as 'optimized' for identifying heart failure individuals.
• This application demonstrates translational utility of the cardiac neuron atlas findings for diagnostic purposes.