Plasma Infrared Fingerprinting Identifies Residual Risk in Coronary Artery Disease and Captures Clonal Haematopoiesis-Associated Biology
M von Scheidt, T Eissa, J Krefting, M Schwab, M Mokry, P Natarajan, J J Fuster, J B Heimlich, A M Zeiher, W T Abplanalp, J L M Bjorkegren, N J Leeper, F Fleischmann, H Schunkert, M ZigmanAbstract
Background
Residual cardiovascular risk remains substantial in patients with coronary artery disease (CAD) despite optimal secondary prevention. Clonal haematopoiesis of indeterminate potential (CHIP) contributes causally to this risk but requires sequencing for detection. Plasma infrared molecular fingerprinting (IMF), a spectroscopy-based assay, was evaluated as a sequencing-free tool for residual risk stratification and CHIP-aligned phenotyping.
Methods
A total of 1,341 patients with angiographically confirmed CAD (mean age 73 years, 76% male) were analysed over a follow-up of up to 11 years. Plasma IMF spectra, comprehensive clinical data, and targeted sequencing of 13 CHIP driver genes were measured. Penalised Cox regression models using IMF features were benchmarked against the guideline-recommended SMART2 score. Model performance was assessed by discrimination, reclassification, calibration, and decision-curve analysis. External validations were performed in two independent cohorts (KORA, n = 3,169; Lasers4Life, n = 2,123).
Results
The IMF+Age model demonstrated superior mortality discrimination compared with SMART2 (C-index 0.79 vs. 0.74, P<0.01) and significant reclassification improvement (10-year IDI 0.05, 95% CI 0.03-0.08, P<0.001; NRI 0.69, 95% CI 0.35-1.02, P<0.001). Decision-curve analysis showed greater net benefit across clinical thresholds. IMF-derived risk strata differentiated 11-year survival (3.4%, 11.7%, and 27.1%; log-rank P<0.001) and were enriched for CHIP carriers, particularly spliceosome mutations. External validation reproduced expected risk patterns and comorbidity associations.
Conclusion
Plasma IMF provides a rapid, low-cost, sequencing-free assessment of residual mortality risk in CAD, outperforming guideline-based scores while reflecting CHIP-associated biology. IMF constitutes a scalable phenotypic platform for precision secondary prevention and biology-guided trial design.Graphical abstract