Plasma Infrared Fingerprinting Identifies Residual Risk in Coronary Artery Disease and Captures Clonal Haematopoiesis-Associated Biology

M. von Scheidt (München)¹, T. Eissa (Garching)², J. Krefting (München)³, C. Friess (München)¹, M. Schwab (München)¹, I. Pugach (München)⁴, D. Meyer (Garching)⁵, J. Aschauer (Garching)⁵, Z. Chen (München)¹, G. Hoermann (München)⁶, M. Meggendorfer, (München)⁶, D. Bongiovanni (Augsburg)⁷, D. Breucker (München)⁴, K. Wenger (München)⁴, F. Voll (München)¹, C. Gräßer (München)¹, T. Keßler (München)¹, H. Sager (München)¹, L. Oldenbuettel (München)⁴, L. Maegdefessel (München)⁸, J. S. Hecker (München)⁹, F. Bassermann (München)⁹, M. Sander (München)⁴, S. Holdenrieder (München)¹⁰, I. Hilgendorf (Freiburg im Breisgau)¹¹, F. Leuschner (Heidelberg)¹², S. S. Adkar (Stanford)¹³, C. L. Miller (Charlottesville)¹⁴, M. U. Kaikkonen (Kuopio)¹⁵, M. Mokry (Utrecht)¹⁶, G. Pasterkamp (Utrecht)¹⁷, P. Natarajan (Boston)¹⁸, J. J. Fuster (Madrid)¹⁹, A. Bick (Nashville)²⁰, J. B. Heimlich (Nashville)²⁰, M. A. Rieger (Frankfurt am Main)²¹, S. Cremer (Frankfurt am Main)²², S. Dimmeler (Frankfurt am Main)²³, A. M. Zeiher (Frankfurt am Main)²⁴, W. Abplanalp (Frankfurt am Main)²⁵, J. L. M. Björkegren (Stockholm)²⁶, N. J. Leeper (Stanford)²⁷, B. Linkohr (Neuherberg)²⁸, A. Peters (Neuherberg)²⁹, A. Kastrati (München)¹, S. Cassese (München)³⁰, W. Koenig (München)¹, F. Fleischmann (Garching)², H. Schunkert (München)¹, M. Žigman (Garching)^2
1Deutsches Herzzentrum München Klinik für Herz- und Kreislauferkrankungen München, Deutschland; ²Laboratory for Attosecond Physics, Max Planck Institute of Quantum Optics Garching, Deutschland; ³Deutsches Herzzentrum München Klink für Herzkreislauferkrankungen München, Deutschland; ⁴Deutsches Herzzentrum München, TUM Universitätsklinikum München, Deutschland; ⁵Garching, Deutschland; ⁶MLL Munich Leukemia Laboratory München, Deutschland; ⁷Universitätsklinikum Augsburg I. Medizinische Klinik Augsburg, Deutschland; ⁸Klinikum rechts der Isar der Technischen Universität München Klinik für Vaskuläre und Endovaskuläre Chirurgie München, Deutschland; ⁹Department of Medicine III, TUM Klinikum Rechts der Isar München, Deutschland; ¹⁰Deutsches Herzzentrum München Institut für Laboratoriumsmedizin München, Deutschland; ¹¹Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland; ¹²Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; ¹³Division of Vascular Surgery Department of Surgery Stanford, USA; ¹⁴Department of Genome Sciences, University of Virginia, Charlottesville, USA; ¹⁵A.I. Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio, Finnland; ¹⁶Central Diagnostics Laboratory, University Medical Center Utrecht Utrecht, Niederlande; ¹⁷University Medical Center Utrecht Department of Experimental Cardiology Utrecht, Niederlande; ¹⁸Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital Boston, USA; ¹⁹Centro Nacional de Investigaciones Cardiovasculares Carlos III Madrid, Spanien; ²⁰Department of Medicine, Vanderbilt University Medical Center Nashville, USA; ²¹Universitätsklinikum Frankfurt Med. Klinik II, Hämatologie/Onkologie Frankfurt am Main, Deutschland; ²²Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland; ²³Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; ²⁴Goethe Universität Frankfurt am Main Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland; ²⁵Universitätsklinikum Frankfurt Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; ²⁶Department of Medicine, Huddinge, Karolinska Institutet, Karolinska Universitetssjukhuset Stockholm, Schweden; ²⁷Stanford University School of Medicine Division of Vascular Surgery Stanford, USA; ²⁸Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health Neuherberg, Deutschland; ²⁹Helmholtzzentrum München Neuherberg, Deutschland; ³⁰Deutsches Herzzentrum München München, Deutschland

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.