Even mild elevations of C-reactive protein levels predict long-term prognosis in heart failure with mildly reduced ejection fraction

Clinical Research in Cardiology https://doi.org/10.1007/s00392-026-02958-8 ORIGINAL PAPER Even mild elevations of C‑reactive protein levels predict long‑term prognosis in heart failure with mildly reduced ejection fraction Jonas Dudda1 · Michael Behnes1 · Michelle Goertz1 · Felix Lau1 · Alexander Schmitt1 · Marielen Reinhardt1 · Noah Abel1 · Svetlana Hetjens2 · Daniel Duerschmied1 · Mohammad Abumayyaleh1 · Ibrahim Akin1 · Tobias Schupp1 Received: 2 February 2026 / Accepted: 23 May 2026 © The Author(s) 2026 Abstract Objective C-reactive protein (CRP) levels reflect systemic inflammation which may mediate adverse outcomes in heart failure (HF). The present study sought to investigate the prognostic impact of baseline CRP levels in patients hospitalized with HF with mildly reduced ejection fraction (HFmrEF). Background While inflammation is recognized as a key pathophysiological component of HF, data on the prognostic relevance of CRP in HFmrEF patients remain limited. Methods Consecutive patients hospitalized with HFmrEF were retrospectively included at a single centrer. The primary analysis included unselected all-comer patients, while a secondary analysis excluded patients with conditions associated with increased CRP levels. CRP was analyzed in predefined categories (i.e., <5 mg/L, 5-<10 mg/L, 10-<50 mg/L, ≥50 mg/L) and as a continuous variable (log-transformed). The prognostic impact of CRP levels was investigated with regard to the primary endpoint all-cause mortality at 30 months;, key secondary endpoint was HF-related rehospitalization. Results A total of 1,978 HFmrEF patients were hospitalized with a median CRP level of 13.3 mg/L (interquartile range 3.5–43.7 mg/L). Compared with CRP <5 mg/L, CRP levels of 5–<10 mg/L (HR 1.720; 95% CI 1.250–2.366; p = 0.001), 10–<50 mg/L (HR 1.813; 95% CI 1.400 2.348; p = 0.001), and ≥50 mg/L (HR 2.275; 95% CI 1.731–2.991; p = 0.001) were independently associated with increased all-cause mortality after multivariable adjustment. This association was consistent when CRP was analyzed as a continuous variable ((ln)CRP: HR 1.250; 95% CI 1.167–1.339; p = 0.001), as well after excluding patients with conditions associated with elevated CRP levels. By contrast, CRP was not independently associated with the risk of HF-related rehospitalization. Conclusion In patients hospitalized with HFmrEF, elevated CRP levels, even mild CRP elevations, were independently associated with an increased risk of long-term all-cause mortality. These findings support the prognostic relevance of even low-grade systemic inflammation in HFmrEF. Jonas Dudda and Michael Behnes contributed equally. * Tobias Schupp 1 Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany 2 Institute of Medical Biostatistics, Epidemiology and Informatics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany Vol.:(0123456789) Clinical Research in Cardiology Graphical Abstract Keywords Heart failure · HFmrEF · CRP · Inflammation · Prognosis · Mortality Introduction Heart failure (HF) is one of the leading causes for morbidity and mortality worldwide and is most commonly categorized based on left ventricular ejection fraction (LVEF) [1]. About one quarter of HF patients suffer from HF with mildly reduced ejection fraction (HFmrEF; i.e., LVEF 41–49%), which represents an underrepresented subgroup of HF patients in clinical trials and large registry studies. As a result, guideline recommendations for patients with HFmrEF are limited [2–4]. C-reactive protein (CRP) represents a highly conserved acute-phase protein expressed after hepatic induction due to interleukin-6 (IL-6) stimulation in various inflammatory conditions such as bacterial infection, but also related to rheumatoid or cardiovascular diseases [5–7]. In both patients with acute and chronic HF, systemic inflammation has been recognized as a key pathophysiological feature. For instance, elevated baseline CRP levels were found in 499 patients with stable HF and reduced (HFrEF) or preserved LVEF (HFpEF) (medians 6.6 and 8.5 mg/L) [8], while CRP levels were even higher in patients with acute HF [9]. Moreover, CRP is not exclusively associated with the presence of HF, but also with the risk of developing HF in patients with pre-existing cardiovascular diseases [10, 11]. Notably, as early as 75 years ago, it was shown that CRP was linked to an impaired outcomes in patients with HF in a pivotal study by Elster et al. [12]. Since then, an extensive body of evidence has grown regarding the prognostic impact of CRP in HF [7, 13]. In 794 patients with acute HF, CRP levels at 30 days after admission were associated with all-cause mortality at 180 days [14]. In addition, elevated CRP levels have previously been shown to predict short-term mortality in a cohort of 3831 patients with HF, with consistent findings across the LVEF spectrum when stratified by CRP tertiles [15]. While the short-term prognostic significance of CRP has been evaluated within various acute and chronic HF Clinical Research in Cardiology populations, there is a gap in evidence in the subpopulation of patients with HFmrEF, especially regarding the mid- and long-term predictive value of CRP levels. The present study aims to investigate the prognostic impact of CRP levels in patients hospitalized with HFmrEF with regard to long-term all-cause mortality and HFrelated rehospitalization. Methods Study patients, design, and data collection For the present study, all consecutive patients hospitalized with HFmrEF at one University Medical Centre were included from January 2016 to December 2022. Using the electronic hospital information system, all relevant clinical data related to the index event were documented, such as baseline characteristics, vital signs on admission, prior medical history, prior medical treatment, length of index hospital and intensive care unit (ICU) stay, laboratory values, data derived from all non-invasive or invasive cardiac diagnostics and device therapies, such as echocardiographic data, coronary angiography, and data being derived from prior or newly implanted cardiac devices. The present study was derived from the “Heart Failure with Mildly Reduced Ejection Fraction Registry” (HARMER), representing a retrospective single-center all-comers registry including consecutive patients with HFmrEF hospitalized at the University Medical Centre Mannheim (UMM), Germany (clinicaltrials.gov identifier: NCT05603390). The registry was carried out according to the principles of the declaration of Helsinki and was approved by the medical ethics committee II of the Medical Faculty Mannheim, University of Heidelberg, Germany (ethical approval code: 2022–818). No written informed consent was necessary for the present study. Inclusion and exclusion criteria All consecutive patients with ≥ 18 years of age hos (...truncated)