Cardiac Macrophages and Fibroblasts Modulate Atrial Fibrillation Maintenance.
Summary
Across two porcine PsAF models and human validation, atrial driver regions were enriched for ACTA2- and PTX3-fibroblast phenotypes and resident cardiac macrophages with homeostatic/survival-supporting signatures. Targeted ablation of driver regions terminated AF in most pigs and was associated with 90% AF freedom at 2 years in humans.
Key Findings
- Driver regions showed enrichment of ACTA2-fibroblasts and PTX3-fibroblasts in porcine PsAF, with PTX3-fibroblast enrichment confined to driver areas on paired regional analysis.
- Resident cardiac macrophages with homeostatic/cell-survival gene and proteomic signatures were enriched in driver regions in pigs and humans.
- In vivo mapping-guided ablation acutely terminated PsAF in 12/14 pigs, and human driver ablation yielded 90% AF freedom at 2 years (on/off AADs).
Clinical Implications
Mapping and ablating AF driver regions characterized by specific fibroblast and macrophage states may improve long-term rhythm control beyond conventional lesion sets.
Why It Matters
This work links spatially resolved nonmyocyte phenotypes to AF maintenance and demonstrates translatable targeting with strong clinical signals, advancing mechanistic understanding and interventional strategy.
Limitations
- Nonrandomized human ablation outcomes and modest sample sizes may overestimate effect size
- Mechanistic causality of specific cell states requires interventional perturbation studies
Future Directions
Prospective randomized trials of driver-guided ablation and targeted modulation of fibroblast/macrophage phenotypes; development of clinical mapping biomarkers for driver identification.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- III - Translational cohort evidence across animal models and human validation without randomization
- Study Design
- OTHER