Colchicine Reverses Inflammatory Signatures in CHIP-Positive Coronary Disease: The COLCHIP Trial

Clin Res Cardiol (2026). DOI 10.1007/s00392-026-02870-1
M. von Scheidt (München)¹, M. Schwab (München)¹, J. Krefting (München)², F. Starnecker (München)¹, J. S. Hecker (München)³, C. Gräßer (München)¹, S. Baumann (München)⁴, L. Piermeier (München)³, V. Sanders (Heidelberg)⁵, F. Bassermann (München)³, F. Goessweiner (München)⁶, A. Ehrsam (München)⁶, P. Bauer (München)⁶, L. Oldenbuettel (München)⁶, I. Pugach (München)⁶, C. Friess (München)⁶, D. Breucker (München)⁶, K. Wenger (München)⁶, S. Mahajan (München)⁶, G. Hoermann (München)⁷, M. Meggendorfer, (München)⁷, T. Eissa (Garching)⁸, M. Žigman (Garching)⁸, M. Sander (München)⁶, S. Holdenrieder (München)⁹, J. B. Heimlich (Nashville)¹⁰, A. Bick (Nashville)¹⁰, J. J. Fuster (Madrid)¹¹, P. Natarajan (Boston)¹², C. Sofokleous (Utrecht)¹³, K. C. Palm (Utrecht)¹³, M. Mokry (Utrecht)¹³, G. Pasterkamp (Utrecht)¹⁴, D. Bongiovanni (Augsburg)¹⁵, Z. Chen (München)¹⁶, M. Shumliakivska (Frankfurt)¹⁷, S. Cremer (Frankfurt am Main)¹⁸, S. Dimmeler (Frankfurt)¹⁹, J. L. M. Björkegren (Stockholm)²⁰, N. J. Leeper (Stanford)²¹, A. M. Zeiher (Frankfurt am Main)²², W. Abplanalp (Frankfurt am Main)²³, H. Schunkert (München)¹, W. Koenig (München)^24
1Deutsches Herzzentrum München Klinik für Herz- und Kreislauferkrankungen München, Deutschland; ²Deutsches Herzzentrum München Klink für Herzkreislauferkrankungen München, Deutschland; ³Department of Medicine III, TUM Klinikum Rechts der Isar München, Deutschland; ⁴epartment of Medicine III, TUM Klinikum Rechts der Isar München, Deutschland; ⁵Klinikum rechts der Isar der Technischen Universität München Klinik und Poliklinik für Innere Medizin I Heidelberg, Deutschland; ⁶Deutsches Herzzentrum München, TUM Universitätsklinikum München, Deutschland; ⁷MLL Munich Leukemia Laboratory München, Deutschland; ⁸Laboratory for Attosecond Physics, Max Planck Institute of Quantum Optics Garching, Deutschland; ⁹Deutsches Herzzentrum München Institut für Laboratoriumsmedizin München, Deutschland; ¹⁰Department of Medicine, Vanderbilt University Medical Center Nashville, USA; ¹¹Centro Nacional de Investigaciones Cardiovasculares Carlos III Madrid, Spanien; ¹²Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital Boston, USA; ¹³Central Diagnostics Laboratory, University Medical Center Utrecht Utrecht, Niederlande; ¹⁴University Medical Center Utrecht Department of Experimental Cardiology Utrecht, Niederlande; ¹⁵Universitätsklinikum Augsburg I. Medizinische Klinik Augsburg, Deutschland; ¹⁶TUM Klinikum Rechts der Isar Klinik und Poliklinik für Innere Medizin I München, Deutschland; ¹⁷Department of Medicine, Cardiology, Goethe University Hospital Frankfurt, Deutschland; ¹⁸Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland; ¹⁹Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt, Deutschland; ²⁰Department of Medicine, Huddinge, Karolinska Institutet, Karolinska Universitetssjukhuset Stockholm, Schweden; ²¹Stanford University School of Medicine Division of Vascular Surgery Stanford, USA; ²²Goethe Universität Frankfurt am Main Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland; ²³Universitätsklinikum Frankfurt Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; ²⁴TUM Klinikum Deutsches Herzzentrum Klinik für Herz- und Kreislauferkrankungen München, Deutschland

Aims: Clonal haematopoiesis of indeterminate potential (CHIP) promotes systemic inflammation and residual cardiovascular risk, yet no targeted therapy exists. Low-dose colchicine reduces cardiovascular events through anti-inflammatory effects, but its capacity to modulate mutation-driven inflammation in humans is unknown. The COLCHIP trial tested whether short-term colchicine attenuates inflammatory signatures in CHIP-positive coronary artery disease (CAD).

Methods: COLCHIP was a randomized, double-blind, placebo-controlled, crossover phase 2 trial enrolling 54 patients with stable angiographically proven CAD and CHIP (variant allele frequency ≥2%). Participants received colchicine 0.5 mg daily or matching placebo for 4 weeks each, without washout; 48 completed both treatment periods and were analyzed per protocol. Peripheral blood samples were obtained at baseline, after colchicine exposure, and four weeks after withdrawal. Routine laboratory markers and plasma proteomics (5,416 proteins quantified by dual-batch Olink Explore HT; >95% assay reproducibility) were analyzed using mixed-effects models including treatment, period, and sequence as fixed effects (false-discovery-rate q<0.05). The primary endpoint was the within-subject change in systemic inflammatory protein expression between treatment periods.

Results: Participants (mean age 70 ± 6 years; 81% male) harbored CHIP mutations predominantly in DNMT3A, TET2, or ASXL1. Colchicine significantly reduced total leukocytes (−9%, P=0.023) and neutrophils (−11%, P=0.007) while modestly increasing lymphocytes (P=0.03); values normalized after withdrawal. Proteomic profiling revealed suppression of inflammatory and cytoskeletal pathways, including NF-κB, TNF, IL-6, and leukocyte-adhesion signaling. The secretory glycoprotein WFDC2 consistently decreased, emerging as a robust marker of anti-inflammatory response. Correlation networks between CHIP variant allele frequency and inflammatory proteins were abolished under colchicine and re-emerged after cessation, indicating transient pharmacologic uncoupling of clonal burden from systemic inflammation. No serious adverse events occurred.

Conclusions: COLCHIP is the first prospective randomized anti-inflammatory trial in individuals with CHIP. In CHIP-positive CAD, low-dose colchicine reverses systemic inflammatory and proteomic signatures and transiently disconnects mutant-clone activity from vascular inflammation, demonstrating that genetically driven atherosclerotic inflammation is pharmacologically reversible. These findings provide a mechanistic rationale for incorporating CHIP into cardiovascular prevention strategies and inform the design of future genotype-guided outcome trials evaluating targeted anti-inflammatory therapy.