Prognostic impact of high-sensitivity C-reactive protein trajectories and sustained residual inflammation

B. Kurt (Aachen)¹, M. Reugels (Aachen)¹, K. M. Schneider (Dresden)², F. Wenzl (Zürich)³, C. B. Fordyce (Vancouver)⁴, N. J. Pagidipati (Durham)⁵, V. Rocha (Sao Paulo)⁶, M. Fudim (Durham)⁷, J. Spießhöfer (Aachen)⁸, A. Milzi (Lugano)⁹, M. Lehrke (Traunstein)¹⁰, H. Shimokawa (Sendai)¹¹, G. Liuzzo (Rome)¹², L. Tokgozoglu (Ankara)¹³, F. Crea (Rome)¹⁴, T. F. Lüscher (Zürich)¹⁵, P. Libby (Boston)¹⁶, P. M. Ridker (Boston)¹⁷, N. Marx (Aachen)¹, C. V. Schneider (Aachen)¹⁸, A. Sharma (Montreal)¹⁹, F. Kahles (Aachen)^1
1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; ²Technische Universität Dresden Medizinische Klinik und Poliklinik I Dresden, Deutschland; ³University of Zurich Center for Molecular Cardiology Zürich, Schweiz; ⁴Vancouver General Hospital, University of British Columbia Division of Cardiology, Department of Medicine and the Centre for Cardiovascular Innovation Vancouver, Kanada; ⁵Duke University School of Medicine Duke University Medical Center; Division of Cardiology, Department of Medicine Durham, USA; ⁶University of Sao Paulo Medical School Hospital Heart Institute (Instituto do Coracao (InCor)) Sao Paulo, Deutschland; ⁷Duke Cardiology Clinic - Clinic 2F/2G Durham, USA; ⁸Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; ⁹Istituto Cardiocentro Ticino - EOC Lugano, Schweiz; ¹⁰Klinikum Traunstein Kardiologie Traunstein, Deutschland; ¹¹Tohoku University Graduate School of Medicine Department of Cardiovascular Medicine Sendai, Japan; ¹²Fondazione Policlinico Universitario A. Gemelli – IRCCS and Catholic University of the Sacred Heart
 Department of Cardiovascular Sciences - CUORE Rome, Italien; ¹³Hacettepe University Medical Faculty Department of Cardiology Ankara, Türkei; ¹⁴Catholic University of the Sacred Heart Agostino Gemelli Hospital Rome, Italien; ¹⁵Stiftung für Herz- und Kreislaufforschung Zürich, Schweiz; ¹⁶MassGeneralBrigham Hospital, and Harvard Medical School Heart and Vascular Institute Boston, USA; ¹⁷Brigham and Women’s Hospital Center for Cardiovascular Disease Prevention, Division of Preventive Medicine Boston, USA; ¹⁸Uniklinik RWTH Aachen Med. Klinik III - Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin Aachen, Deutschland; ¹⁹McGill University Division of Cardiology, Research Institute of the McGill University Health Centre Montreal, Kanada

Background: Despite advancing preventive and therapeutic strategies, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality globally. While medical interventions focus on traditional risk factors, these fail to reflect fully the residual risk observed in many individuals. The risk of cumulative exposure to atherogenic lipoproteins or elevated blood pressure has been well described before. However, the prognostic impact of longitudinal inflammatory burden, quantified by serial high-sensitivity C-reactive protein (hsCRP) levels, remains incompletely understood. In individuals in a steady state, hsCRP concentrations generally remain stable. But some individuals may experience increases, related to heightened systemic inflammation. More information on whether sustained, increasing, or decreasing inflammation as measured by hsCRP provides prognostic information above traditional risk factors may improve our understanding of how persistent inflammation drives residual cardiovascular risk.

Methods: In this population-based cohort study, sequential hsCRP measurements were available in 15 967 UK Biobank participants without known history of ASCVD. The guideline-recommended hsCRP cut-off value of 2 mg/L defined individuals with low-grade inflammation. To assess the primary outcome of all-cause death Kaplan-Meier and Cox proportional hazards analyses with restricted cubic splines were used.

Results: During a median observation time of 15.3 years, all-cause death occurred in 884 subjects. Median time between baseline (T₀) and follow-up (T₁) hsCRP measurement was 4.4 years. When participants were stratified according to longitudinal changes in hsCRP groups (<2 mg/L vs. ≥2 mg/L), mortality risk differed significantly (log-rank p<0.001). Individuals with persistently elevated hsCRP (“stayed inflamed”) had the highest mortality risk, followed by those with newly increased hsCRP (“newly inflamed”), while participants whose hsCRP decreased (“less inflamed”) and those with consistently low hsCRP (“non-inflamed”) showed the lowest risk. Compared with participants who remained non-inflamed, those with persistent inflammation had the highest mortality risk, with more than a twofold increase (HR: 2.19; 95% CI: 1.87, 2.56; p<0.001). Those who became inflamed had a 65% higher risk of death (HR: 1.65; 95% CI: 1.35; 2.01; p<0.001) and those who showed a decline in inflammation had the lowest risk (HR: 1.41; 95% CI: 1.13, 1.75; p<0.001). Multivariable adjustment for age, sex, BMI, type 2 diabetes mellitus, smoking, systolic blood pressure, LDL cholesterol and eGFR demonstrated a largely independent association of these results.

Conclusion: In this population-based longitudinal assessment of hsCRP, sustained or newly developed low-grade inflammation identified individuals at higher risk of death, beyond traditional cardiovascular risk factors. These findings emphasize the prognostic importance of cumulative persistent inflammation as a marker of residual cardiovascular risk and highlight the potential clinical value of serial hsCRP measurements to improve long-term risk stratification and preventive strategies.