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Vol 18, No 4 (2023)
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The new face of HFpEF: systemic inflammation

Małgorzata Lelonek1
Folia Cardiologica 2023;18(4):161-164.


Systemic inflammation is proposed as background of development and progres of heart failure, especially in heart failure with preserved ejection fraction (HFpEF). High-sensitivity C-reactive protein seems to be an optimal biomarker of systemic inflammation. Knowledge of systemic inflammation is important for new therapeutic fields in HFpEF with potential in inhibition of IL-1β, IL-6 or galectin-3.


Folia Cardiologica 2023

vol. 18, no. 4, pages 161–164

DOI: 10.5603/fc.96384

Copyright © 2023 Via Medica

ISSN 2353–7752

e-ISSN 2353–7760

The new face of HFpEF: systemic inflammation

Małgorzata Lelonek
Department of Noninvasive Cardiology, Medical University of Lodz, Łódź, Poland

Address for correspondence: Prof. Małgorzata Lelonek MD, PhD, FESC, FHFA, Zakład Kardiologii Nieinwazyjnej, Uniwersytet Medyczny w Łodzi, ul. Żeromskiego 113, 90–549 Łódź, Poland, tel. 42 639 37 93, e-mail: malgorzata.lelonek@umed.lodz.pl

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Systemic inflammation is proposed as background of development and progres of heart failure, especially in heart failure with preserved ejection fraction (HFpEF). High-sensitivity C-reactive protein seems to be an optimal biomarker of systemic inflammation. Knowledge of systemic inflammation is important for new therapeutic fields in HFpEF with potential in inhibition of IL-1β, IL-6 or galectin-3.
Key words: HFpEF, systemic inflammation
Folia Cardiologica 2023; 18, 4: 161–164

There has been a lot of recent progress in heart failure with preserved ejection fraction (HFpEF), leading to changes in therapeutic approaches. This is due to positive results from two major trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors: EMPEROR-Preserved and DELIVER [1, 2]. These are the first studies dedicated to HF with an EF > 40% that have demonstrated clinical benefits in terms of reducing the risk of cardiovascular death and/or worsening HF (hospitalisation due to HF exacerbation, exacerbation without hospitalisation but requiring increased diuretic doses).

For many years, the distinct pathophysiology of HFpEF compared to heart failure with reduced ejection fraction (HFrEF) has been emphasised. Recent years have focused on understanding the phenomenon of systemic inflammation [3] and its significance in HFpEF. According to current knowledge in cardiology, inflammatory processes play a role in the development and progression of HF, are of particular importance in HFpEF, especially in certain subphenotypes. This was proven in the COACH (Counseling in Heart Failure) and BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) studies [4, 5]. This association is likely related to a higher burden of comorbidities in HFpEF, such as diabetes, hypertension, obesity, and chronic kidney disease. The current concept indicates the involvement of systemic inflammation in myocardial remodeling in HFpEF (Paulus paradigm) with inflammation at the level of small vessels (microvascular inflammation) [6].

A promising biomarker for identifying systemic inflammation is high-sensitivity C-reactive protein (hsCRP). Measurement of CRP levels using a high-sensitivity method allows the detection of low-grade inflammatory processes with CRP levels of 2–10 mg/L. This was the focus of studies in which elevated levels of this biomarker were documented in populations with both acute and stable clinical presentations of HF (Table 1). Interleukin 6 (IL-6), which stimulates CRP production, was found to be associated with atrial fibrillation (OR 1.35; 95% CI: 1.03–1.77; p = 0.028), lower glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, and worse exercise tolerance among 2329 patients in the BIOSTAT-CHF study [11]. Higher IL-6 levels were also associated with HFpEF (OR 1.63; 95% CI: 1.06–2.5; p = 0.027) and had predictive value for mortality (OR 1.22; 95% CI: 1.16–1.29; p < 0.001). Each doubling of IL-6 was an independent risk factor for hospitalisation for HF and cardiovascular death and all-cause mortality at 2-year follow-up (HR 1.16; 95% CI: 1.11–1.21; p < 0.001). The IL-6 signaling pathway seems to be particularly relevant for HFpEF [11].

Table 1. Review of selected trials evaluating inflammatory processes in heart failure

Trial name


Inflammatory biomarkers



Elevated CRP levels in 57% of the population


Elderly patients HFrEF HFpEF

Median hsCRP 6.6 mg/L 8.5 mg/L



Median hsCRP 12.6 mg/L



33 biomarkers from various pathophysiological pathways (inflammation, oxidative stress, remodeling, cardiac stretch, angiogenesis, atherosclerosis, and kidney function)


Post-heart attack patients





Another important factor is the role of epicardial adipose tissue (EAT) as a direct inducer of systemic inflammation [12]. The MESA study [13], which included 6785 individuals without cardiovascular diseases, revealed that the presence of epicardial adipose tissue in cardiac computed tomography was a predictor of HFpEF development (log rank p < 0.001) but not HFrEF (log rank p = 0.1) in a long-term follow-up (> 15 years).

Understanding the phenomenon of systemic inflammation is crucial for identifying new treatment options, such as inhibition of IL-1β, IL-6, or galectin-3. According to the studies conducted so far for IL-1β blockade, there was a significant 38% reduction in the risk of hospitalisation for HF and death from any cause for those patients who responded to therapy with canakinumab (documented reduction in hsCRP levels < 2 mg/L) compared to the placebo group (CANTOS trial) [10]. Currently, there is an ongoing study using the IL-6 inhibitor, ziltivekimab — a monoclonal antibody against IL-6 — in the HFpEF population [14].

However, it is still an open question what effect weight loss has on the inhibition of HF progression and the severity of systemic inflammation. This year will be the completion of two studies on semaglutide in the HFpEF population — the STEP-HFpEF and STEP-DM trials [15], which may answer this question. The STEP programme is the first to evaluate the effect of once-weekly semaglutide at a dose of 2.4 mg on symptoms, physical capacity, and functional improvement in obese HFpEF patients. A total of 1146 patients with obesity and HFpEF were randomised in the STEP-HFpEF programme [15].

In conclusion, SGLT2 inhibitors have revolutionised the approach to HF across the spectrum. Thanks to landmark trials like EMPEROR-Preserved and DELIVER, we now have therapy dedicated to patients with HF and an EF > 40% [1, 2, 16]. The published Heart Failure Association European Society of Cardiology (HFA ESC) position statement jointly with the European Heart Rhythm Association and the European Society of Hypertension on profiling patients with HFpEF to tailor therapy with a central position of SGLT2 inhibitors and diuretics in case of congestion (Figure 1), was one of the most important reports of this year’s HFA ESC Congress [17]. Nonetheless, the search for HFpEF therapies — particularly considering systemic inflammation as a therapeutic target — continues.

Figure 1. Profiling heart failure with preserved ejection fraction patients for personalized treatment [16]; ACEi — angiotensin-converting enzyme inhibitors; ARB — angiotensin receptor blocker; ARNi — angiotensin receptor neprilysin inhibitor; CKD — chronic kidney disease; COPD — chronic obstructive pulmonary disease; GLP1-RA — glucagon-like peptide 1 receptor agonists; LABA — long-acting β-agonist; LAMA — long-acting muscarinic receptor antagonist; MRA — mineralcorticoid receptor antagonist; PVI — pulmonary vein isolation

Article information



Author contributions

ML — 100%.

Conflict of interest

Lectures and trials fee — Boehringer Ingelheim; lectures — Novo Nordisk, lectures and experts fee — AstraZeneca.



Supplementary material



  1. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021; 385(16): 1451–1461, doi: 10.1056/NEJMoa2107038, indexed in Pubmed: 34449189.
  2. Salomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022; 387(12): 1089–1098, doi: 10.1056/NEJMoa2206286, indexed in Pubmed: 36027570.
  3. Murphy SP, Kakkar R, McCarthy CP, et al. Inflammation in Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020; 75(11): 1324–1340, doi: 10.1016/j.jacc.2020.01.014, indexed in Pubmed: 32192660.
  4. Tromp J, Khan MAF, Klip IT, et al. Biomarker Profiles in Heart Failure Patients With Preserved and Reduced Ejection Fraction. J Am Heart Assoc. 2017; 6(4), doi: 10.1161/JAHA.116.003989, indexed in Pubmed: 28360225.
  5. Tromp J, Westenbrink BD, Ouwerkerk W, et al. Identifying Pathophysiological Mechanisms in Heart Failure With Reduced Versus Preserved Ejection Fraction. J Am Coll Cardiol. 2018; 72(10): 1081–1090, doi: 10.1016/j.jacc.2018.06.050, indexed in Pubmed: 30165978.
  6. van Heerebeek L, Paulus WJ, Paulus WJ, et al. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013; 62(4): 263–271, doi: 10.1016/j.jacc.2013.02.092, indexed in Pubmed: 23684677.
  7. Redfield MM, Chen HH, Borlaug BA, et al. RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a rando­mized clinical trial. JAMA. 2013; 309(12): 1268–1277, doi: 10.1001/jama.2013.2024, indexed in Pubmed: 23478662.
  8. Pfisterer M, Buser P, Rickli H, et al. TIME-CHF Investigators. BNP- –guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA. 2009; 301(4): 383––392, doi: 10.1001/jama.2009.2, indexed in Pubmed: 19176440.
  9. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011; 365(1): 32–43, doi: 10.1056/NEJMoa1100171, indexed in Pubmed: 21732835.
  10. Everett BM, Cornel JH, Lainscak M, et al. Anti-Inflammatory Therapy With Canakinumab for the Prevention of Hospitalization for Heart Failure. Circulation. 2019; 139(10): 1289–1299, doi: 10.1161/CIRCULATIONAHA.118.038010, indexed in Pubmed: 30586730.
  11. Markousis-Mavrogenis G, Tromp J, Ouwerkerk W, et al. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Eur J Heart Fail. 2019; 21(8): 965–973, doi: 10.1002/ejhf.1482, indexed in Pubmed: 31087601.
  12. Packer M. Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium. J Am Coll Cardiol. 2018; 71(20): 2360–2372, doi: 10.1016/j.jacc.2018.03.509, indexed in Pubmed: 29773163.
  13. Kenchaiah S, Ding J, Carr JJ, et al. Pericardial Fat and the Risk of Heart Failure. J Am Coll Cardiol. 2021; 77(21): 2638–2652, doi: 10.1016/j.jacc.2021.04.003, indexed in Pubmed: 34045020.
  14. https://classic.clinicaltrials.gov/ct2/show/NCT05636176.
  15. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Design and Baseline Characteristics of STEP-HFpEF Program Evaluating Semaglutide in Patients With Obesity HFpEF Phenotype. JACC Heart Fail. 2023 [Epub ahead of print], doi: 10.1016/j.jchf.2023.05.010, indexed in Pubmed: 37294245.
  16. Kittleson MM, Panjrath GS, Amancherla K, et al. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023; 81(18): 1835–1878, doi: 10.1016/j.jacc.2023.03.393, indexed in Pubmed: 37137593.
  17. Anker SD, Usman MS, Anker MS, et al. Patient phenotype profiling in heart failure with preserved ejection fraction to guide therapeutic decision making. A scientific statement of the Heart Failure Association, the European Heart Rhythm Association of the European Society of Cardiology, and the European Society of Hypertension. Eur J Heart Fail. 2023 [Epub ahead of print], doi: 10.1002/ejhf.2894, indexed in Pubmed: 37461163.