Deciphering the cardiac neuron landscape in heart failure patients

Area of Science:

• Cardiovascular Biology
• Neuroscience
• Genomics

Background:

• Cardiac neurons are crucial for heart function, but their role in cardiac dysfunction remains unclear.
• Understanding the molecular mechanisms of cardiac neurons in heart failure is essential for developing new therapies.

Purpose of the Study:

• To create a comprehensive cardiac neuron atlas using single-nucleus RNA sequencing data.
• To identify and characterize distinct neuronal subsets in healthy and failing hearts.
• To explore the specific roles of identified neuron subsets in heart failure pathogenesis.

Main Methods:

• Integrated single-nucleus RNA sequencing data from 75 heart failure patients and 45 healthy donors.
• Analyzed 11,026 neuronal cells to identify distinct subsets.
• Investigated the transcriptional regulatory network and cell-cell crosstalk involving identified neuron subsets.

Main Results:

• Identified ten distinct neuronal cell subsets with varying abundances and functions in the heart.
• Found N4-ALK neurons significantly enriched in failing hearts, correlating with left ventricular assist device response.
• Discovered the PTN-PTPRZ1 axis mediates crosstalk between cardiac fibroblasts and N4-ALK neurons in heart failure.
• Developed a predictive model for heart failure identification based on N4-ALK neuron features.

Conclusions:

• The cardiac neuron atlas provides a detailed molecular and functional characterization of cardiac neurons.
• N4-ALK neurons represent a key cell type implicated in heart failure.
• This research offers novel perspectives on neuronal regulation in cardiac dysfunction and potential therapeutic targets.