Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability.

Area of Science:

• Cardiovascular Biology
• Molecular Pathology
• Genomics and Transcriptomics

Background:

• Traditional characterization of vulnerable coronary atherosclerotic plaques relies on cellular architecture.
• Emerging intravascular imaging reveals novel coronary thrombosis mechanisms, challenging current acute coronary syndrome (ACS) understanding.
• A precise molecular definition of plaque stability is crucial for advancing ACS research.

Purpose of the Study:

• To investigate the vascular microenvironment in patients with stable versus unstable coronary plaques.
• To utilize spatial transcriptomics to define molecular differences associated with plaque stability.

Main Methods:

• Analysis of autopsy-derived coronary arteries categorized by plaque stability using the GeoMx spatial profiling platform.
• Whole Transcriptome Atlas was employed to link histological markers with differential gene expression in specific regions of interest.
• Spatially resolved transcriptional profiling and cell morphological analysis were performed, preserving intercellular signaling.

Main Results:

• Distinct spatial and cell-specific transcriptional patterns were observed in stable and unstable plaques, with regional variations in the intima and media.
• Differential expression of proinflammatory molecules (e.g., interferon-γ, MHC class II) and prothrombotic pathways were identified.
• Unique intraplaque subpopulations from endothelial, smooth muscle, and myeloid lineages were characterized, linked to plaque instability and calcification.

Conclusions:

• The study identifies distinct cell-specific and regional transcriptional alterations in unstable coronary plaques.
• Spatially resolved in situ evidence supports cellular transdifferentiation and intraplaque plasticity as contributors to plaque instability.
• Results offer a resource for identifying novel mediators of ACS and developing new preventative/therapeutic strategies.