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. 2025 Oct 15:102712.
doi: 10.1016/j.jchf.2025.102712. Online ahead of print.

Prevalence and Associations of Systemic Inflammation in Heart Failure Across the Spectrum of Ejection Fraction

Barry A Borlaug  1 , Cecilie Holse  2 , Mette Holme Jung  2 , A Michael Lincoff  3 , Sharon L Mulvagh  4 , Jacob Stærk-Østergaard  2 , Katherine R Tuttle  5 , Mark C Petrie  6
Affiliations

Prevalence and Associations of Systemic Inflammation in Heart Failure Across the Spectrum of Ejection Fraction

Barry A Borlaug et al. JACC Heart Fail. .

Abstract

Background: Systemic inflammation contributes to the pathophysiology of heart failure (HF). Inflammation in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) has been linked to cardiovascular-kidney-metabolic conditions, whereas inflammation in heart failure and reduced ejection fraction (HFrEF) is thought to develop secondary to cardiac stress and circulatory derangements.

Objectives: This study aims to characterize the prevalence and correlates of systemic inflammation across the spectrum of HF.

Methods: Patients with HF participating in 3 large outcome trials (SELECT, SOUL, and FLOW) were examined to identify the prevalence of systemic inflammation, defined as elevated high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L. Clinical characteristics associated with elevated hsCRP were examined by HF subtype and across the HF spectrum.

Results: Across the 3 trials, 3,204 patients had HFpEF, 1,246 had HFmrEF, and 1,018 had HFrEF. Elevated hsCRP was observed in 2,335 patients (52.5%) with HFpEF/HFmrEF and 503 patients (49.4%) with HFrEF. Compared with patients with lower hsCRP levels, those with higher hsCRP levels were more likely to be female and have obesity, diabetes, lower estimated glomerular filtration rate, higher albuminuria, and chronic obstructive pulmonary disease, without meaningful differences by HF subtype. hsCRP level was unrelated to ejection fraction (R2 < 0.001; P = 0.73) but increased linearly with the number of comorbidities for all HF subtypes (R2 = 0.94; P < 0.001).

Conclusions: Systemic inflammation is present in one-half of patients with HF, and is associated with excess body fat, chronic kidney disease, albuminuria, and diabetes, and increases with comorbidity burden. These relationships are not specific to HFpEF/HFmrEF but are also common to HFrEF (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity [SELECT]; NCT03574597; A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153; A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes [SOUL]; NCT03914326).

Keywords: C-reactive protein; HFmrEF; HFpEF; HFrEF; cardiometabolic; heart failure; inflammation; kidney; obesity.

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Conflict of interest statement

Funding Support and Author Disclosures This study was funded by Novo Nordisk A/S. Dr Borlaug is supported by R01 HL128526, R01 HL162828, and U01 HL160226 from the National Heart, Lung, and Blood Institute, W81XWH2210245 from the United States Department of Defense, and the Schoen Foundation; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (US patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Drs Holse, Jung, and Stærk-Østergaard are employees of Novo Nordisk A/S. Dr Lincoff has received research funding from Esperion, Eli Lilly, AbbVie, CSL, AstraZeneca, and Novartis; and consulting fees from Novo Nordisk, Eli Lilly, Akebia, Alnylam, Amgen, Ardelyx, Becton-Dickson, Brainstorm Cell, Cadrenal, Endologix, FibroGen, GlaxoSmithKline, Intarcia, Medtronic, Neovasc, Provention Bio, and ReCor. Dr Mulvagh has received consulting fees from Novo Nordisk and Lantheus Medical Imaging. Dr Tuttle is supported by National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, and OT2OD032581; is supported by CDC project numbers 75D301-21-P-12254 and 75D301-23-C-18264; has received investigator-initiated grant support from Travere, Bayer, and the Doris Duke Foundation outside the submitted work; has received consultancy fees from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and has received speaker fees from Novo Nordisk. Dr Petrie has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and has consulted and/or served on committees for Abott, Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Corteria, Novartis, AstraZeneca, Novo Nordisk, AbbVie, Bayer, Horizon Therapeutics, Foundry, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, 3R Lifesciences, Reprieve, FIRE 1, and Corvia.

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