- 1Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- 2Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
- 3Rheumatology Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, Bari, Italy
- 4Department of Engineering for Innovative Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
- 5Department of Medicine-Catholic University of the Sacred Heart, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Importance: Heart failure with preserved ejection fraction (HFpEF), defined by an ejection fraction >50%, has emerged as the most prevalent form of heart failure at the community level. Multiple comorbidities, including diabetes, hypertension, obesity, atrial fibrillation, renal diseases, and autoimmune conditions, have been linked to its development. These conditions share common pathways involving oxidative stress, metabolic dysregulation, ischemia, and a chronic inflammatory milieu.
Observations: Patients with autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) exhibit an increased risk of developing HFpEF, often through mechanisms involving chronic inflammation and endothelial dysfunction, which precede the clinical manifestation of HFpEF. Clinical studies have demonstrated that the risk of developing HFpEF exists independently of traditional cardiovascular risk factors, underscoring the pivotal role of chronic inflammation and autoimmunity as key contributors to its pathogenesis.
Conclusions and relevance: The translational implication is that the distinct inflammatory pathways driving these autoimmune diseases (e.g., myeloid-T cells and T-B cell-mediated inflammation in RA, and B cell-driven inflammation in SLE and SSc) should become personalized therapeutic targets to prevent HFpEF progression. Early intervention with novel therapies, such as sodium-glucose cotransporter type 2 (SGLT2) inhibitors, could be crucial in managing these patients during the early disease stages. Additionally, the H2FPEF score should be routinely employed to facilitate early diagnosis and risk stratification, providing a robust framework for personalized management strategies.
Introduction
Heart failure with preserved ejection fraction (HFpEF) has emerged as a leading cause of mortality among heart failure patients (1). According to the current guidelines of the American Heart Association/American College of Cardiology and the European Society of Cardiology, the diagnosis of HFpEF is based on three primary criteria: 1. the presence of signs and symptoms consistent with heart failure; 2. a preserved left ventricular ejection fraction (LVEF ≥50%); and 3. objective evidence of impaired left ventricular (LV) diastolic function (2). Estimates suggest that at least 50% (range 44–72%) of all heart failure cases occur with preserved ejection fraction (3).
Community-based data from Olmsted County indicate that only 16% of HFpEF patients had a prior myocardial infarction, compared to 28% of those with heart failure with reduced ejection fraction (HFrEF). Additionally, coronary heart disease accounted for 29% of deaths in HFpEF patients compared to 43% in HFrEF patients (4). These findings suggest that coronary artery disease plays a less dominant role in HFpEF, while myocardial disease appears to be more prevalent. Between 2000 and 2010, the proportion of HFpEF among new heart failure cases in Olmsted County increased from 48 to 52%, with women being affected twice as often as men. Furthermore, over this decade, the incidence of HFpEF showed a smaller decline compared to HFrEF (−27 versus −61%, respectively) (5).
HFpEF is generally characterized by older age, female predominance, and a higher prevalence of atrial fibrillation, with lower rates of stroke and coronary artery disease (1). Its global prevalence is rising, driven by both traditional risk factors (i.e., obesity, diabetes, hypertension, smoking, metabolic syndrome, renal failure, anemia), and emerging pathophysiological mechanisms, including diastolic dysfunction, endothelial dysfunction, microvascular damage, and systemic low-grade inflammation that promotes myocardial remodeling (3, 6). Oxidative stress and fibrosis are also recognized as critical contributors to the disease’s pathogenesis (7).
Inflammation plays a pivotal role in the development of heart failure, potentially contributing differently to its various subtypes, with evidence highlighting a specific association between the interleukin-6 (IL-6)/C-reactive protein (CRP) pathway and the pathogenesis of HFpEF (8). In inflammatory and autoimmune rheumatologic diseases, HFpEF remains underrecognized, despite evidence suggesting that its development may be driven by distinct autoimmune and inflammatory mechanisms specific to each condition.
Therefore, in this review, we focus on evidence from the past two decades (2004–2024) exploring the intersection of HFpEF and three autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). Specifically, we conducted a literature search using PubMed and Scopus, covering the years 2004–2024. Search terms included “HFpEF,” “diastolic dysfunction,” “autoimmune,” “rheumatoid arthritis,” “SLE,” and “systemic sclerosis.” We included english-language studies focusing specifically on HFpEF in the context of autoimmune diseases, ultimately identifying five studies in RA, seven prospective studies overall, and one observational study with relevant clinical data. We excluded studies that did not clearly distinguish between HFpEF and HFrEF, or that lacked primary data on cardiovascular outcomes.
Endothelial dysfunction, chronic inflammation, diastolic dysfunction, and HFpEF: experimental models
While not all diastolic dysfunctions (DD) progress to HFpEF, all HFpEF cases exhibit DD (9). Understanding the pathophysiology of DD is therefore crucial to elucidate its progression to heart failure. An ideal murine model of HFpEF should present specific characteristics, such as exercise intolerance, pulmonary edema, concentric cardiac hypertrophy, and a preserved EF > 50% (10). Among the proposed models, three particularly emphasize the link between DD and inflammation.
In Goto-Kakizaki (GK) rats, a prediabetic model with insulin deficiency, DD originates in the myofilaments. Synchrotron radiation small-angle X-ray scattering (SAXS) on beating hearts revealed displacement of myosin heads from actin filaments during diastole, along with impaired relaxation and cross-bridge dynamics (11, 12). Mitochondrial oxidative stress and elevated activity of protein kinase C (PKC) and Rho kinase (ROCK) increase cardiomyocyte stiffness and passive tension, ultimately promoting DD (13). Oxidative stress acts as a secondary messenger, activating PKC (14) and the Rho/ROCK pathway (15), which in turn trigger NF-κB and AP-1 activation. These pathways promote cytokine and growth factor transcription, extracellular matrix (ECM) remodeling, vasospasm, hypertension, and myocardial remodeling (16, 17) (Figure 1).

Figure 1. During inflammatory response, in the mytochondrial environment, oxidative stress activates PKC and Rho/ROCK pathway, subsequently triggering cellular NF-κB and AP-1, which drive inflammatory cascades. Thus, contributes to the development of coronary vasospasm, hypertension, and myocardial remodeling, ultimately resulting in diastolic dysfunction. PKC, protein kinase C; NF-κB, nuclear factor kappa light chain of B cells; AP-1, activator protein-1; ECM, extracellular matrix.
Notably, GK rats showed elevated myocardial IL-6, TGF-β1, and Nox2 (a ROS-producing enzyme). Despite these changes, eNOS and NO-mediated vasodilation were preserved. These findings establish oxidative stress and inflammation as central mechanisms driving DD and endothelial dysfunction (13, 17). Likewise, in women with ischemia but no coronary artery disease, oxidative stress has been linked to DD (18).
Diabetes further contributes to DD via chronic low-grade inflammation, termed “metabolic inflammation” (19). Once DD develops, its association with ED becomes evident (20, 21), and ED has emerged as a promising therapeutic target in heart failure (22).
Additional validated models of DD include the SAUNA model (salty water, unilateral nephrectomy, aldosterone) and an aging murine model. In both, increased hematopoiesis correlates with macrophage recruitment and elevated ROS production. These macrophages secrete TGF-β and IL-10, promoting fibroblast activation and ECM synthesis (e.g., type I collagen, α-SMA) (23, 24).
Resident cardiac macrophages (RCMs), classified as CCR2 + or CCR2-, play differential roles. CCR2- macrophages aid repair and angiogenesis (25), while CCR2 + macrophages fuel inflammation through IL-1β and Nlrp3 activation, contributing to adverse remodeling (26). In failing human hearts, CCR2 + cells dominate, enriched in NF-κB, IL-6, and STAT3 pathways (27, 28). These cells also express oncostatin M (OSM), known to inhibit myoblast differentiation, especially after ischemic injury (27). Single-cell RNA-seq studies confirmed their pro-inflammatory role (28).
Thus, even conditions like hypertension and aging contribute to cardiac injury and DD, largely through inflammation-driven mechanisms.
In conclusion, the pathophysiology of HFpEF encompasses cardiomyocyte stiffness, fibrosis, microvascular dysfunction, oxidative stress, and chronic inflammation. As stated by Paulus and Tschope (29), all comorbidities associated with HFpEF appear to converge on a shared inflammatory axis that sustains myocardial dysfunction (Figure 2).

Figure 2. Traditional and non-traditional risk factors leading to diastolic dysfunction and to heart failure with preserved ejection fraction. eGFR, estimated glomerular filtration rate; NSAIDs, non-steroidal anti-inflammatory drugs; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; NTproBNP, N-terminal pro–B-type natriuretic peptide; BSA, body surface area.
This section emphasizes that inflammation is a unifying mechanism across diverse HFpEF models and sets the stage for exploring human clinical phenotypes.
HFpEF human phenotypes
These experimental insights highlight how inflammation initiates and perpetuates the pathophysiology of HFpEF and justify exploration of clinical phenotypes linked to such mechanisms. The relationship between HFpEF and comorbidities is well-documented beyond aging (30, 31). Across cohorts, approximately 45% of HFpEF patients have diabetes (32), 80% in the US are obese (33), 40–60% present with atrial fibrillation/flutter (34, 35), 55% have hypertension (36–38), and 26–49% have renal disease (39, 40). These comorbidities collectively create a low-to-moderate inflammatory state. Combined with neurohormonal, metabolic, and ischemic factors, this milieu promotes myocardial stiffness via oxidative stress, ischemia, and inflammation (Table 1).

Table 1. Experimental models and in vivo human phenotypes of endothelial and diastolic dysfunction ending up to HFpEF.
Understanding these phenotypes helps contextualize the relevance of inflammation in HFpEF and paves the way to analyze autoimmune conditions in the following sections.
Chronic inflammation, autoimmunity, and the heart
Understanding the role of systemic inflammatory burden across populations helps translate experimental evidence into clinical relevance.
Chronic heart inflammation, unlike acute myocarditis, is typically driven by autoimmune diseases, which vary in inflammatory load and vascular involvement. Analyzing cardiovascular comorbidities in these conditions provides valuable insights into how chronic inflammation contributes to HFpEF.
Several studies have shown that the risk of acute myocardial infarction (AMI) in rheumatoid arthritis (RA) rivals that of type 2 diabetes (41), and that heart failure (HF) risk is doubled in RA compared to the general population (42). The QRISK 3 algorithm now includes RA and systemic lupus erythematosus (SLE) in its 10-year cardiovascular risk estimation (43). Additionally, persistent inflammation—as measured by high-sensitivity CRP—has been shown to better predict cardiovascular events and mortality than LDL cholesterol in statin-treated patients (44).
Notably, the Reynolds score used in women also incorporates hsCRP, linking inflammation and cardiovascular risk. CRP is strongly associated with endothelial dysfunction (ED) in hyperlipidemic individuals (45), reinforcing the tight interplay among inflammation, lipids, and endothelial damage.
Together, these observations build a strong rationale for focusing on vascular inflammation as a shared pathway driving HFpEF in autoimmune diseases.
Autoimmunity, chronic inflammation, and diastolic dysfunction
Diastolic dysfunction (DD) affects approximately 28.1% of the general population (46), where it independently predicts mortality and heart failure (47, 48). In autoimmune diseases, DD is even more prevalent and strongly associated with disease features.
For example, in RA, DD was observed in 31% of patients and linked to disease duration and elevated IL-6 levels (49). Premenopausal RA patients showed an even higher prevalence (47%) compared to age-matched controls (26%), with CRP being the strongest independent predictor (50).
In PsA, DD prevalence reached 38%, associated with older age and hypertension (51). In SSc, DD affected 35% of patients, regardless of whether disease was limited or diffuse, and correlated with Raynaud’s duration (52).
In SLE, 39% had DD independent of disease activity (SELENA-SLEDAI), with disease duration being the strongest determinant, while the Framingham score proved unreliable (53). Anti-cardiolipin antibodies, especially LAC, predicted worse DD progression (54).
Similarly, in IBD, DD was associated with reduced coronary flow reserve (CFR), an indicator of microvascular function (55), and cardiovascular risk has been recognized by expert panels (56).
These findings consistently show that autoimmune and chronic inflammatory diseases are strong contributors to DD, reinforcing the importance of cardiovascular monitoring in these patients.
Endothelial dysfunction in autoimmune-chronic inflammatory diseases: a screening of diastolic dysfunction?
The 2013 paradigm by Paulus and Tschöpe (29) proposed that cardiovascular risk factors induce systemic inflammation, which impairs endothelial and coronary microvascular function, ultimately leading to HFpEF. This is supported by histological evidence of microvascular rarefaction and NOX2 expression in macrophages from HFpEF patients (57), as well as high prevalence of vascular dysfunction in this condition (58). Accordingly, autoimmune diseases frequently exhibit ED. Specifically:
1. RA: impaired response to acetylcholine, reversible with TNF-α blockade; long-term improvement requires disease remission (59, 60).
2. SSc: ED reversible with endothelin A receptor antagonism, but not with nitroprusside (61).
3. SLE: reduced FMD, worsened by comorbidities (62, 63).
4. PMR: FMD remained low even after 6 months of treatment, inversely correlated with CRP (64).
Normal FMD is ~6.4%, with age-related decline (65); standardized protocols now enable its use as a biomarker (66). Moreover, prospective studies show that ED predicts DD progression (67), and DD precedes HFpEF (48). Hence, maintaining control of systemic inflammation (as in RA and SLE) is essential (60, 68).
All together, these data support the concept of ED as an early and actionable marker in the prevention of HFpEF among patients with chronic autoimmune inflammation.
HFpEF in rheumatoid arthritis, lupus and systemic sclerosis
While DD and ED are well-documented in autoimmune diseases, the clinical burden of HFpEF is only recently emerging as a distinct phenotype. Multiple studies from 2008 to 2024 have demonstrated that HFpEF is the dominant HF subtype in these populations (69–73) (Table 2). In RA, one-year mortality after HF diagnosis was 35%, compared to 19% in controls (69), and incidence ranged from 2.5 to 8.2% across cohorts (70–72). These risks remained stable over decades and were linked to disease activity.
Similarly, HF incidence was higher in RA (4.87/1,000 person-years vs. 3.96 in controls) (73). In other autoimmune diseases, HFpEF also emerged as the predominant phenotype. For instance, the Athero-APS study showed an increasing gradient of HFpEF prevalence from asymptomatic aPL carriers (6.3%) to full-blown SLE-APS (27.8%) (74). Large population studies confirmed that HF risk is markedly elevated in SSc, SLE, and RA (75), with worse in-hospital outcomes for SLE patients (76). In SSc, 27% met HFpEF criteria, and interstitial lung disease was a key predictor (77). Up to 70.5% of patients with autoimmune HF had the preserved EF phenotype (78).
Interestingly, RA patients on biologics were more likely to recover EF (78), but those with autoimmune comorbidities had a 3x higher risk of mortality or hospitalization (79). The underlying inflammatory drivers differ: RA involves myeloid–T and T–B cell inflammation (80, 81), SLE and SSc involve B-cell-mediated pathways (82–85).
Thus, therapies should reflect this heterogeneity: IL-6 blockers show promise in ischemic damage (86), T cell costimulation blockade prevents age-related dysfunction (87), and B-cell depletion has improved dilated cardiomyopathy (88).
This highlights the need for a personalized, inflammation-targeted approach in preventing and managing HFpEF in autoimmune disease.
Evidence and perspectives
Controlling inflammation has emerged as a crucial strategy for improving diastolic dysfunction and potentially preventing HFpEF. Animal studies have offered compelling evidence supporting this approach. In a model of HFpEF using DAHL/SS salt-sensitive hypertensive rats, the administration of colchicine significantly improved survival, reduced cardiac dysfunction, and diminished oxidative stress and inflammatory cell infiltrates (89). These findings suggest the potential efficacy of colchicine, with human trials expected to provide further clarification (90).
Among the most promising emerging therapies, sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated clinical benefits in HFpEF, particularly in patients with comorbid conditions such as type 2 diabetes and obesity. Results from large randomized trials, including EMPEROR-Preserved (91) and DELIVER (92), showed that treatment with empagliflozin or dapagliflozin significantly reduced the risk of heart failure hospitalization and cardiovascular death. These effects are thought to arise from improved myocardial energetics, decreased preload and afterload, and anti-inflammatory as well as antifibrotic properties. While data specifically addressing autoimmune populations are currently lacking, the potential of SGLT2 inhibitors to modulate endothelial dysfunction and low-grade systemic inflammation suggests they may also benefit patients with autoimmune-driven HFpEF. Nonetheless, clinicians should be cautious of adverse effects, including genital infections, volume depletion, and ketoacidosis, particularly in elderly or non-obese individuals (Figure 3). Further studies are needed to explore the safety and efficacy of these agents in this specific subgroup.

Figure 3. SGLT2 inhibitors have demonstrated clinical benefits in HFpEF, reducing the risk of heart failure hospitalization and cardiovascular death by modulating endothelial dysfunction and low-grade systemic inflammation, leading to improve myocardial energetics, decrease preload and afterload, and thought anti-inflammatory and antifibrotic properties. Nonetheless, adverse effects include genital infections, volume depletion, and ketoacidosis. SGLT2, sodium-glucose cotransporter 2; HFpEF, heart failure with preserved ejection fraction.
Plasma IL-6 has been a focal point of recent research, with its levels showing a strong predictive value for HFpEF but not for HFrEF in the PREVEND cohort—a prospective study of 961 participants. This association persisted even after adjusting for key risk factors, suggesting IL-6 as a potential target for novel therapeutic strategies (93). Supporting this, IL-6 was found to be an independent predictor of all-cause mortality in hospitalized HFpEF patients, even after accounting for B-type natriuretic peptide (BNP) levels (94). Furthermore, tocilizumab, an IL-6 receptor antagonist, demonstrated improvements in left ventricular ejection fraction in rheumatoid arthritis patients without overt cardiac symptoms, reinforcing the potential benefits of targeting IL-6 (95).
However, the results of targeting inflammation in HFpEF have been mixed. Anakinra, an IL-1 receptor antagonist targeting IL1α/β, failed to improve cardiac function in obese HFpEF patients, despite successfully lowering CRP and NT-proBNP levels (96). Similarly, the CANTOS trial, which investigated canakinumab (an anti-IL1β therapy), found that higher IL-6 levels 3 months post-initiation were associated with a substantial increase in major adverse cardiovascular events (MACE) and all-cause mortality (97), complicating the role of IL-1β inhibition in this context.
The link between inflammation and NT-proBNP levels provides additional insight. Among participants in the MESA study, IL-6 levels were significantly correlated with NT-proBNP levels, although it remains unclear whether these increases directly reflect the risk of incident HFpEF (98).
Of particular interest is the emerging evidence regarding IL-17. A preliminary study indicated that secukinumab, an IL-17A inhibitor, improved inflammation and diastolic dysfunction, which was present in nearly 39% of patients (99). If confirmed, this finding is especially significant given the central role of IL-17 in autoimmune inflammatory diseases (100) and its established involvement in inducing ventricular arrhythmias in ischemic heart failure (101). In addition, both IL-17 and IL-6 were identified as independent predictors of DD progression in patients with normal left ventricular ejection fraction who underwent invasive hemodynamic assessment (102).
Conclusions and research agenda
Compelling evidence underscores the pivotal role of inflammation in the development of HFpEF. Endothelial dysfunction emerges as a critical early biomarker, signaling the onset of microvascular damage that can progress to diastolic dysfunction and ultimately HFpEF. Despite these insights, there is a notable absence of clinical trials focused on identifying the optimal diagnostic approach for early detection of DD and stratifying patients for targeted therapeutic protocols based on the type and intensity of underlying inflammation.
No long-term studies have yet evaluated whether tailored treatments can reduce HFpEF incidence in patients with autoimmune chronic inflammatory diseases such as RA, SLE, or SSc. Additionally, the field lacks consensus on key diagnostic thresholds, such as the cutoff values for assessing DD or levels of natriuretic peptides (e.g., NT-proBNP) indicative of imminent HFpEF (103). Research should prioritize defining whether NT-proBNP levels warrant routine annual evaluation, particularly in older patients. The importance of early biomarker evaluation is further highlighted by data from the U.S. National Inpatient Sample Database (2016–2020), which showed that SLE patients hospitalized with acute decompensated heart failure—whether HFpEF or HFrEF—had a mean age of 61 years, compared to 72 years for non-SLE patients. SLE patients also exhibited higher in-hospital mortality rates, emphasizing the need for timely identification of predictive biomarkers to guide early interventions (104).
This approach gains urgency in the context of ACIDs coexisting with metabolic comorbidities such as type 2 diabetes or obesity, particularly in aging populations, where the cumulative risk of HF increases significantly (103). These scenarios reflect the additive impact of metabolic dysfunction and chronic inflammation on cardiac damage. Addressing this, a cardio-immuno-rheumatologic framework should be integrated into clinical practice (105, 106), ensuring that patients with persistent active inflammation are systematically monitored for HFpEF risk.
For diagnostic precision, the H2FPEF score—a composite tool combining clinical and echocardiographic parameters—offers a valuable approach. This scoring system can predict HFpEF with up to 95% probability when the score exceeds 5/9 (Table 3). Implementing such algorithms could revolutionize screening and management strategies in ACIDs, ensuring timely intervention for patients at elevated cardiovascular risk.

Table 3. H2FPEF score to evaluate the possible presence of HFpEF in patients with symptomatic dyspnea.
Future research must focus on:
1. Longitudinal studies evaluating the impact of targeted anti-inflammatory therapies on HFpEF incidence across RA, SLE, and SSc.
2. Establishing evidence-based thresholds for biomarkers like NT-proBNP to guide routine screening.
3. Developing and validating diagnostic algorithms that integrate inflammatory markers, clinical parameters, and imaging data to improve early identification and risk stratification.
By addressing these gaps, we can move closer to a personalized, proactive approach in preventing HFpEF, particularly in high-risk populations.
Finally, considering the heterogeneity of the available studies, particularly regarding HFpEF definitions, patient populations, and outcome measures, as well as the scarcity of randomized controlled trials in autoimmune settings, our conclusions should be interpreted with caution. These limitations further underscore the urgent need for disease-specific, prospective investigations.
Author contributions
EG: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing. DB: Data curation, Resources, Visualization, Writing – original draft, Writing – review & editing. SP: Data curation, Resources, Visualization, Writing – original draft, Writing – review & editing. JC: Data curation, Validation, Writing– review & editing. GF: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Gen AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2025.1557312/full#supplementary-material
References
1. Andersson, C, and Vasan, RS. Epidemiology of heart failure with preserved ejection fraction. Heart Fail Clin. (2014) 10:377–88. doi: 10.1016/j.hfc.2014.04.003
2. Heidenreich, PA, Bozkurt, B, Aguilar, D, Allen, LA, Byun, JJ, Colvin, MM, et al. Correction to: 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. (2023) 147:e674. doi: 10.1161/CIR.0000000000001142, Erratum for: Circulation. 2022; 145(18): e895–e1032. doi: 10.1161/CIR.0000000000001063
3. Dunlay, SM, Roger, VL, and Redfield, MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. (2017) 14:591–602. doi: 10.1038/nrcardio.2017.65
4. Henkel, DM, Redfield, MM, Weston, SA, Gerber, Y, and Roger, VL. Death in heart failure: a community perspective. Circ Heart Fail. (2008) 1:91–7. doi: 10.1161/CIRCHEARTFAILURE.107.743146
5. Gerber, Y, Weston, SA, Redfield, MM, Chamberlain, AM, Manemann, SM, Jiang, R, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med. (2015) 175:996–1004. doi: 10.1001/jamainternmed.2015.0924
6. Triposkiadis, F, Butler, J, Abboud, FM, Armstrong, PW, Adamopoulos, S, Atherton, JJ, et al. The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J. (2019) 40:2155–63. doi: 10.1093/eurheartj/ehz158
7. Wong, CN, Gui, XY, and Rabkin, SW. Myeloperoxidase, carnitine, and derivatives of reactive oxidative metabolites in heart failure with preserved versus reduced ejection fraction: a meta-analysis. Int J Cardiol. (2024) 399:131657. doi: 10.1016/j.ijcard.2023.131657
8. Albar, Z, Albakri, M, Hajjari, J, Karnib, M, Janus, SE, and Al-Kindi, SG. Inflammatory markers and risk of heart failure with reduced to preserved ejection fraction. Am J Cardiol. (2022) 167:68–75. doi: 10.1016/J.amjcard.2021.11.045
9. Wenzel, JP, Bei der Kellen, R, Magnussen, C, Blankenberg, S, Schrage, B, Schnabel, R, et al. Diastolic dysfunction in individuals with and without heart failure with preserved ejection fraction. Clin Res Cardiol. (2022) 111:416–27. doi: 10.1007/s00392-021-01907-x
10. Valero-Munoz, M, Backman, W, and Sam, F. Murine models of heart failure with preserved ejection fraction: a "fishing expedition". JACC Basic Transl Sci. (2017) 2:770–89. doi: 10.1016/j.jacbts.2017.07.013
11. Shirai, M, Schwenke, DO, Tsuchimochi, H, Umetani, K, Yagi, N, and Pearson, JT. Synchrotron radiation imaging for advancing our understanding of cardiovascular function. Circ Res. (2013) 112:209–21. doi: 10.1161/CIRCRESAHA.111.300096
12. Jenkins, MJ, Pearson, JT, Schwenke, DO, Edgley, AJ, Senobe, T, Fujii, Y, et al. Myosin heads are displaced from actin filaments in the in situ beating rat heart in early diabetes. Biophys J. (2013) 104:1065–72. doi: 10.1016/j.bpj.2013.01.037
13. Waddingham, MT, Sonobe, T, Tsuchimoki, H, Tsuchimoki, H, Edgley, AJ, Sukumaran, V, et al. Diastolic dysfunction is initiated by cardiomyocyte impairment ahead of endothelial dysfunction due to increased oxidative stress and inflammation in an experimental prediabetes model. J Mol Cell Cardiol. (2019) 137:119–31. doi: 10.1016/j.yjmcc.2019.10.005
14. Lien, CF, Chen, SL, Tsai, MC, Lin, CS, Lien, CF, Chen, SJ, et al. Potential role of protein kinase C in the pathophysiology of diabetes-associated atherosclerosis. Front Pharmacol. (2021) 12:716332. doi: 10.3389/fphar.2021.716332
15. Noma, K, Goto, C, Nishioka, K, Jiitsuiki, D, Umemura, T, Ueda, K, et al. Roles of rho-associated kinase and oxidative stress in the pathogenesis of aortic stiffness. J Am Coll Cardiol. (2007) 49:698–705. doi: 10.1016/j.jacc.2006.06.082
16. Perona, R, Montaner, S, Saniger, L, Sánchez-Pérez, I, Bravo, R, and Lacal, JC. Activation of the nuclear factor-kappaB by rho, CDC42, and Rac-1 proteins. Genes Dev. (1997) 11:463–75. doi: 10.1101/gad.11.4.463
17. Raad, M, AlBadri, A, Wei, J, Mehta, PK, Maughan, J, Gadh, A, et al. Oxidative stress is associated with diastolic dysfunction in women with ischemia with no obstructive coronary artery disease. J Am Heart Assoc. (2020) 9:e015602. doi: 10.1161/JAHA.119.015602
18. Elmarakby, AA, and Sullivan, JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther. (2012) 30:49–59. doi: 10.1111/j.1755-5922.2010.00218.x
19. Hotamisligil, GS. Inflammation, metaflammation and immunometabolic disorders. Nature. (2017) 542:177–85. doi: 10.1038/nature21363
20. Gamrat, A, Surdacki, MA, Chyrchel, B, and Surdacki, A. Endothelial dysfunction: a contributor to adverse cardiovascular Remodeling and heart failure development in type 2 diabetes beyond accelerated Atherogenesis. J Clin Med. (2020) 9:2090. doi: 10.3390/jcm9072090
21. Sušić, L, Maričić, L, Šahinović, I, Kralik, K, Klobučar, L, Ćosić, M, et al. The relationship of left ventricular diastolic dysfunction and asymmetrical Dimethylarginine as a biomarker of endothelial dysfunction with cardiovascular risk assessed by systematic coronary risk Evaluation2 algorithm and heart failure-a cross-sectional study. Int J Environ Res Public Health. (2023) 20:4433. doi: 10.3390/ijerph20054433
22. Premer, C, Kanelidis, AJ, Hare, JM, and Schulman, IH. Rethinking endothelial dysfunction as a crucial target in fighting heart failure. Mayo Clin Proc Innov Qual Outcomes. (2019) 3:1–13. doi: 10.1016/j.mayocpiqo.2018.12.006
23. Schauer, A, Adams, V, Kämmerer, S, Langner, E, Augstein, A, Barthel, P, et al. Empagliflozin improves diastolic function in HFpEF by Restabilizing the mitochondrial respiratory chain. Circ Heart Fail. (2024) 17:e011107. doi: 10.1161/CIRCHEARTFAILURE.123.011107
24. Hulsmans, M, Sager, HB, Roh, JD, Valero-Muñoz, M, Houstis, NE, Iwamoto, Y, et al. Cardiac macrophages promote diastolic dysfunction. J Exp Med. (2018) 215:423–40. doi: 10.1084/jem.20171274
25. Wong, NR, Mohan, J, Kopecky, BJ, Guo, S, Du, L, Leid, J, et al. Resident cardiac macrophages mediate adaptive myocardial remodeling. Immunity. (2021) 54:2072–2088.e7. doi: 10.1016/j.immuni.2021.07.003
26. Zaman, R, and Epelman, S. Resident cardiac macrophages: heterogeneity and function in health and disease. Immunity. (2022) 55:1549–63. doi: 10.1016/j.immuni.2022.08.009
27. Xiao, F, Wang, H, Fu, X, Li, Y, Ma, K, Sun, L, et al. Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration. Cell Res. (2011) 21:350–64. doi: 10.1038/cr.2010.144
28. Bajpai, G, Bredemeyer, A, Zaitsev, K, Zaitzev, K, Koenig, AL, Lockshina, I, et al. Tissue resident CCR2- and CCR2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ Res. (2019) 124:263–78. doi: 10.1161/CIRCRESAHA.118.314028
29. Paulus, WJ, and Tschope, C. 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) 62:263–71. doi: 10.1016/j.jacc.2013.02.092
30. Gottdiener, JS, McClelland, RL, Marshall, R, Shemanski, L, Furberg, CD, Kitzman, DW, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The cardiovascular health study. Ann Intern Med. (2002) 137:631–9. doi: 10.7326/0003-4819-137-8-200210150-00006
31. Bursi, F, Weston, SA, Redfield, MM, Jacobsen, SJ, Pakhomov, S, Nkomo, VT, et al. Systolic and diastolic heart failure in the community. JAMA. (2006) 296:2209–16. doi: 10.1001/jama.296.18.2209
32. McHugh, K, DeVore, AD, Wu, J, Matsouaka, RA, Fonarow, GC, Heidenreich, PA, et al. Heart failure with preserved ejection fraction and diabetes: JACC state-of-the-art review. J Am Coll Cardiol. (2019) 73:602–11. doi: 10.1016/j.jacc.2018.11.033
33. Obokata, M, Reddy, YNV, Pislaru, SV, Melenovsky, V, and Borlaug, BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation. (2017) 136:6–19. doi: 10.1161/CIRCULATIONAHA.116.026807
34. Fauchier, L, Bisson, A, and Bodin, A. Heart failure with preserved ejection fraction and atrial fibrillation: recent advances and open questions. BMC Med. (2023) 21:54. doi: 10.1186/s12916-023-02764-3
35. Aldaas, OM, Malladi, CL, and Hsu, JC. Atrial fibrillation in patients with heart failure with preserved ejection fraction. Curr Opin Cardiol. (2020) 35:260–70. doi: 10.1097/HCO.0000000000000732
36. Yancy, CW, Lopatin, M, Stevenson, LW, De Marco, T, and Fonarow, GCADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the acute decompensated heart failure national registry (ADHERE) database. J Am Coll Cardiol. (2006) 47:76–84. doi: 10.1016/j.jacc.2005.09.022 Erratum in: J Am Coll Cardiol. 2006; 47(7): 1502.
37. Gheorghiade, M, Abraham, WT, Albert, NM, Greenberg, BH, O'Connor, CM, She, L, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA. (2006) 296:2217–26. doi: 10.1001/jama.296.18.2217
38. Lee, DS, Gona, P, Vasan, RS, Larson, MG, Benjamin, EJ, Wang, TJ, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham heart study of the national heart, lung, and blood institute. Circulation. (2009) 119:3070–7. doi: 10.1161/CIRCULATIONAHA.108.815944
39. Brouwers, FP, de Boer, RA, van der Harst, P, Voors, AA, Gansevoort, RT, Bakker, SJ, et al. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J. (2013) 34:1424–31. doi: 10.1093/eurheartj/eht066
40. Damman, K, Perez, AC, Anand, IS, Komajda, M, McKelvie, RS, Zile, MR, et al. Worsening renal function and outcome in heart failure patients with preserved ejection fraction and the impact of angiotensin receptor blocker treatment. J Am Coll Cardiol. (2014) 64:1106–13. doi: 10.1016/j.jacc.2014.01.087
41. Lindhardsen, J, Ahlehoff, O, Gislason, GH, Madsen, OR, Olesen, JB, Torp-Pedersen, C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis. (2011) 70:929–34. doi: 10.1136/ard.2010.143396
42. Park, E, Griffin, J, and Bathon, JM. Myocardial dysfunction and heart failure in rheumatoid arthritis. Arthritis Rheumatol. (2022) 74:184–99. doi: 10.1002/art.41979
43. Hippisley-Cox, J, Coupland, C, and Brindle, P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ. (2017) 357:j2099. doi: 10.1136/bmj.j2099
44. Ridker, PM, Bhatt, DL, Pradhan, AD, Glynn, RJ, MacFadyen, JG, Nissen, SE, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. (2023) 401:1293–301. doi: 10.1016/S0140-6736(23)00215-5
45. Cheng, HM, Ye, ZX, Chiou, KR, Lin, SJ, and Charng, MJ. Vascular stiffness in familial hypercholesterolaemia is associated with C-reactive protein and cholesterol burden. Eur J Clin Investig. (2007) 37:197–206. doi: 10.1111/j.1365-2362.2007.01772.x
46. Redfield, MM, Jacobsen, SJ, Burnett, JC Jr, Mahoney, DW, Bailey, KR, and Rodeheffer, RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. (2003) 289:194–202. doi: 10.1001/jama.289.2.194
47. Halley, CM, Houghtaling, PL, Khalil, MK, Thomas, JD, and Jaber, WA. Mortality rate in patients with diastolic dysfunction and normal systolic function. Arch Intern Med. (2011) 171:1082–7. doi: 10.1001/archinternmed.2011.244
48. Kane, GC, Karon, BL, Mahoney, DW, Redfield, MM, Roger, VL, Burnett, JC Jr, et al. Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA. (2011) 306:856–63. doi: 10.1001/jama.2011.1201
49. Liang, KP, Myasoedova, E, Crowson, CS, Davis, JM, Roger, VL, Karon, BL, et al. Increased prevalence of diastolic dysfunction in rheumatoid arthritis. Ann Rheum Dis. (2010) 69:1665–70. doi: 10.1136/ard.2009.124362
50. Kim, GH, and Park, YJ. Accelerated diastolic dysfunction in premenopausal women with rheumatoid arthritis. Arthritis Res Ther. (2021) 23:247. doi: 10.1186/s13075-021-02629-1
51. Shang, Q, Tam, LS, Yip, GW, Sanderson, JE, Zhang, Q, Li, EK, et al. High prevalence of subclinical left ventricular dysfunction in patients with psoriatic arthritis. J Rheumatol. (2011) 38:1363–70. doi: 10.3899/jrheum.101136
52. Hachulla, AL, Launay, D, Gaxotte, V, de Groote, P, Lamblin, N, Devos, P, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis. (2009) 68:1878–84. doi: 10.1136/ard.2008.095836
53. Leone, P, Cicco, S, Prete, M, Solimando, AG, Susca, N, Crudele, L, et al. Early echocardiographic detection of left ventricular diastolic dysfunction in patients with systemic lupus erythematosus asymptomatic for cardiovascular disease. Clin Exp Med. (2020) 20:11–9. doi: 10.1007/s10238-019-00600-8
54. Myhr, KA, Zinglersen, AH, Hermansen, MF, Jepsen, MM, Iversen, KK, Ngo, AT, et al. Left ventricular size and function in patients with systemic lupus erythematosus associate with lupus anticoagulant: an echocardiographic follow-up study. J Autoimmun. (2022) 132:102884. doi: 10.1016/j.jaut.2022.102884
55. Caliskan, Z, Gokturk, HS, Caliskan, M, Gullu, H, Ciftci, O, Ozgur, GT, et al. Impaired coronary microvascular and left ventricular diastolic function in patients with inflammatory bowel disease. Microvasc Res. (2015) 97:25–30. doi: 10.1016/j.mvr.2014.08.003
56. Zanoli, L, Mikhailidis, DP, Bruno, RM, Abreu, MT, Danese, S, Eliakim, R, et al. Aortic stiffening is an Extraintestinal manifestation of inflammatory bowel disease: review of the literature and expert panel statement. Angiology. (2020) 71:689–97. doi: 10.1177/0003319720918509
57. Franssen, C, Chen, S, Unger, A, Korkmaz, HI, De Keulenaer, GW, Tschöpe, C, et al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail. (2016) 4:312–24. doi: 10.1016/j.jchf.2015.10.007
58. Tona, F, Montisci, R, Iop, L, and Civieri, G. Role of coronary microvascular dysfunction in heart failure with preserved ejection fraction. Rev Cardiovasc Med. (2021) 22:97–104. doi: 10.31083/j.rcm.2021.01.277
59. Cardillo, C, Schinzari, F, Mores, N, Mettimano, M, Melina, D, Zoli, A, et al. Intravascular tumor necrosis factor alpha blockade reverses endothelial dysfunction in rheumatoid arthritis. Clin Pharmacol Ther. (2006) 80:275–81. doi: 10.1016/j.clpt.2006.05.011
60. Bosello, S, Santoliquido, A, Zoli, A, Di Campli, C, Flore, R, Tondi, P, et al. TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis. Clin Rheumatol. (2008) 27:833–9. doi: 10.1007/s10067-007-0803-y
61. Cardillo, C, Schinzari, F, Melina, D, Mores, N, Bosello, S, Peluso, G, et al. Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosis. Arthritis Rheum. (2009) 60:1840–4. doi: 10.1002/art.24502
62. Mak, A, Know, NY, Schwarz, H, Gong, L, Tay, SH, and Ling, LH. Endothelial dysfunction in systemic lupus erythematosus – a case-control study and an updated meta-analysis and meta-regression. Sci Rep. (2017) 7:7320. doi: 10.1038/s41598-017-07574-1
63. Mendoza-Pinto, C, Rojas-Villarraga, A, Molano-González, N, García-Carrasco, M, Munguía-Realpozo, P, Etchegaray-Morales, I, et al. Endothelial dysfunction and arterial stiffness in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Atherosclerosis. (2020) 297:55–63. doi: 10.1016/j.atherosclerosis.2020.01.028
64. Santoro, L, Birra, D, Bosello, S, Nesci, A, Di Giorgio, A, Peluso, G, et al. Subclinical atherosclerosis and endothelial dysfunction in patients with polymyalgia rheumatica: a pilot study. Scand J Rheumatol. (2020) 49:68–74. doi: 10.1080/03009742.2019.1628297
65. Heiss, C, Rodriguez-Mateos, A, Bapir, M, Skene, SS, Sies, H, and Kelm, M. Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health. Cardiovasc Res. (2023) 119:283–93. doi: 10.1093/cvr/cvac095
66. Alexander, Y, Osto, E, Schmidt-Trucksäss, A, Shechter, M, Trifunovic, D, Duncker, DJ, et al. Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on atherosclerosis and vascular biology, aorta and peripheral vascular diseases, coronary pathophysiology and microcirculation, and thrombosis. Cardiovasc Res. (2021) 117:29–42. doi: 10.1093/cvr/cvaa085
67. Ma, LN, Zhao, SP, Gao, M, Zhou, QC, and Fan, P. Endothelial dysfunction associated with left ventricular diastolic dysfunction in patients with coronary heart disease. Int J Cardiol. (2000) 72:275–9. doi: 10.1016/s0167-5273(99)00203-x
68. Parker, B, Al-Husain, A, Pemberton, P, Yates, AP, Ho, P, Gorodkin, R, et al. Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus. Ann Rheum Dis. (2014) 73:1144–50. doi: 10.1136/annrheumdis-2012-203028
69. Davis, JM 3rd, Roger, VL, Crowson, CS, Kremers, HM, Therneau, TM, and Gabriel, SE. The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheum. (2008) 58:2603–11. doi: 10.1002/art.23798
70. Huang, S, Cai, T, Weber, BN, He, Z, Dahal, KP, Hong, C, et al. Association between inflammation, incident heart failure, and heart failure subtypes in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). (2023) 75:1036–45. doi: 10.1002/acr.24804
71. Mantel, Ä, Holmqvist, M, Andersson, DC, Lund, LH, and Askling, J. Association between rheumatoid arthritis and risk of ischemic and nonischemic heart failure. J Am Coll Cardiol. (2017) 69:1275–85. doi: 10.1016/j.jacc.2016.12.033
72. Myasoedova, E, Kurmann, RD, Achenbach, SJ, Wright, K, Arment, CA, Dunlay, SM, et al. Trends in incidence of chronic heart failure in patients with rheumatoid arthritis: a population-based study validating different heart failure definitions. J Rheumatol. (2023) 50:881–8. doi: 10.3899/jrheum.221170
73. Ahlers, MJ, Lowery, BD, Farber-Eger, E, Wang, TJ, Bradham, W, Ormseth, MJ, et al. Heart failure risk associated with rheumatoid arthritis-related chronic inflammation. J Am Heart Assoc. (2020) 9:e014661. doi: 10.1161/JAHA.119.014661
74. Pastori, D, Ames, PRJ, Triggiani, M, Ciampa, A, Cammisotto, V, Carnevale, R, et al. Antiphospholipid antibodies and heart failure with preserved ejection fraction. The Multicenter ATHERO-APS study. J Clin Med. (2021) 10:3180. doi: 10.3390/jcm10143180
75. Prasada, S, Rivera, A, Nishtala, A, Pawlowski, AE, Sinha, A, Bundy, JD, et al. Differential associations of chronic inflammatory diseases with incident heart failure. JACC Heart Fail. (2020) 8:489–98. doi: 10.1016/j.jchf.2019.11.013
76. Nomigolzar, S, Nomigolzar, R, El Sharu, H, and Subramanian, L. Impact of systemic lupus erythematosus on outcomes in patients hospitalized with acute decompensated heart failure with reduced and preserved ejection fraction: a national inpatient sample study. Eur Heart J. (2016) 44:ehad 655.1140. doi: 10.1093/eurheartj/ehad655.1140
77. Fontes Oliveira, M, Rei, AL, Oliveira, MI, Almeida, I, and Santos, M. Prevalence and prognostic significance of heart failure with preserved ejection fraction in systemic sclerosis. Futur Cardiol. (2022) 18:17–25. doi: 10.2217/fca-2020-0238
78. Rivera, AS, Sinha, A, Ahmad, FS, Thorp, E, Wilcox, JE, Lloyd-Jones, DM, et al. Long-term trajectories of left ventricular ejection fraction in patients with chronic inflammatory diseases and heart failure: an analysis of electronic health records. Circ Heart Fail. (2021) 14:e008478. doi: 10.1161/CIRCHEARTFAILURE.121.008478
79. Tada, A, Doi, S, Harada, T, Ibe, T, Naser, JA, Amdahl, M, et al. Autoimmune disorders in heart failure with preserved ejection fraction. JACC Heart Fail. (2024) 12:1257–69. doi: 10.1016/j.jchf.2024.04.016
80. Alivernini, S, Firestein, GS, and McInnes, IB. The pathogenesis of rheumatoid arthritis. Immunity. (2022) 55:2255–70. doi: 10.1016/j.immuni.2022.11.009
81. Bucci, L, Hagen, M, Rothe, T, Raimondo, MG, Fagni, F, Tur, C, et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med. (2024) 30:1593–601. doi: 10.1038/s41591-024-02964-1
82. Müller, F, Taubmann, J, Bucci, L, Wilhelm, A, Bergmann, C, Völkl, S, et al. CD19 CAR T-cell therapy in autoimmune disease – a case series with follow-up. N Engl J Med. (2024) 390:687–700. doi: 10.1056/NEJMoa2308917
83. Isaacs, JD. CAR T cells – a new horizon for autoimmunity? N Engl J Med. (2024) 390:758–9. doi: 10.1056/NEJMe2400203
84. Arbitman, L, Furie, R, and Vashistha, H. B cell-targeted therapies in systemic lupus erythematosus. J Autoimmun. (2022) 132:102873. doi: 10.1016/j.jaut.2022.102873
85. Bosello, S, De Luca, G, Tolusso, B, Lama, G, Angelucci, C, Sica, G, et al. B cells in systemic sclerosis: a possible target for therapy. Autoimmun Rev. (2011) 10:624–30. doi: 10.1016/j.autrev.2011.04.013
86. Huse, C, Anstensrud, AK, Michelsen, AE, Ueland, T, Broch, K, Woxholt, S, et al. Interleukin-6 inhibition in ST-elevation myocardial infarction: immune cell profile in the randomised ASSAIL-MI trial. EBioMedicine. (2022) 80:104013. doi: 10.1016/j.ebiom.2022.104013
87. Martini, E, Cremonesi, M, Panico, C, Carullo, P, Bonfiglio, CA, Serio, S, et al. T cell Costimulation blockade blunts age-related heart failure. Circ Res. (2020) 127:1115–7. doi: 10.1161/CIRCRESAHA.119.316530
88. Tschöpe, C, Van Linthout, S, Spillmann, F, Posch, MG, Reinke, P, Volk, HD, et al. Targeting CD20+ B-lymphocytes in inflammatory dilated cardiomyopathy with rituximab improves clinical course: a case series. Eur Heart J Case Rep. (2019) 3:ytz131. doi: 10.1093/ehjcr/ytz131
89. Shen, S, Duan, J, Hu, J, Qi, Y, Kang, L, Wang, K, et al. Colchicine alleviates inflammation and improves diastolic dysfunction in heart failure rats with preserved ejection fraction. Eur J Pharmacol. (2022) 929:175126. doi: 10.1016/j.ejphar.2022.175126
90. Bourcier, L, Bellemare, M, Tremblay-Gravel, M, Henri, C, White, M, and Bouabdallaoui, N. Effects of COLchicine on inflammation, myocardial damage and microvascular dysfunction in heart failure with preserved ejection fraction – the COLpEF trial. Arch Cardiovasc Dis Suppl. (2023) 15:53. doi: 10.1016/j.acvdsp.2022.10.097
91. Anker, SD, Butler, J, Filippatos, G, Ferreira, JP, Bocchi, E, Böhm, M, et al. EMPEROR-preserved trial investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. (2021) 385:1451–61. doi: 10.1056/NEJMoa2107038
92. Solomon, SD, McMurray, JJV, Claggett, B, de Boer, RA, DeMets, D, Hernandez, AF, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. (2022) 387:1089–98. doi: 10.1056/NEJMoa2206286
93. Chia, YC, Kieneker, LM, van Hassel, G, Binnenmars, SH, Nolte, IM, van Zanden, JJ, et al. Interleukin 6 and development of heart failure with preserved ejection fraction in the general population. J Am Heart Assoc. (2021) 10:e018549. doi: 10.1161/JAHA.120.018549
94. Mooney, L, Jackson, CE, Adamson, C, McConnachie, A, Welsh, P, Myles, RC, et al. Adverse outcomes associated with Interleukin-6 in patients recently hospitalized for heart failure with preserved ejection fraction. Circ Heart Fail. (2023) 16:e010051. doi: 10.1161/CIRCHEARTFAILURE.122.010051
95. Kobayashi, H, Kobayashi, Y, Giles, JT, Yoneyama, K, Nakajima, Y, and Takei, M. Tocilizumab treatment increases left ventricular ejection fraction and decreases left ventricular mass index in patients with rheumatoid arthritis without cardiac symptoms: assessed using 3.0 tesla cardiac magnetic resonance imaging. J Rheumatol. (2014) 41:1916–21. doi: 10.3899/jrheum.131540
96. Van Tassell, BW, Trankle, CR, Canada, JM, Carbone, S, Buckley, L, Kadariya, D, et al. IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ Heart Fail. (2018) 11:e005036. doi: 10.1161/CIRCHEARTFAILURE.118.005036
97. Ridker, PM, MacFadyen, JG, Thuren, T, and Libby, P. Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur Heart J. (2020) 41:2153–63. doi: 10.1093/eurheartj/ehz542
98. Fish-Trotter, H, Ferguson, JF, Patel, N, Arora, P, Allen, NB, Bachmann, KN, et al. Inflammation and circulating natriuretic peptide levels. Circ Heart Fail. (2020) 13:e006570. doi: 10.1161/CIRCHEARTFAILURE.119.006570
99. Huangfu, L, Li, R, Huang, Y, and Wang, S. The IL-17 family in diseases: from bench to bedside. Signal Transduct Target Ther. (2023) 8:402. doi: 10.1038/s41392-023-01620-3
100. Makavos, G, Ikonomidis, I, Andreadou, I, Varoudi, M, Kapniari, I, Loukeri, E, et al. Effects of interleukin 17A inhibition on myocardial deformation and vascular function in psoriasis. Can J Cardiol. (2020) 36:100–11. doi: 10.1016/j.cjca.2019.06.021
101. Chang, SL, Hsiao, YW, Tsai, YN, Lin, SF, Liu, SH, Lin, YJ, et al. Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure. J Mol Cell Cardiol. (2018) 122:69–79. doi: 10.1016/j.yjmcc.2018.08.005
102. Xu, L, Yan, J, Zhang, F, Zhou, C, Fan, T, Chen, X, et al. Use of inflammatory biomarkers and real-time cardiac catheterisation to evaluate the left ventricular diastolic function in patients with diastolic heart failure. Heart Lung Circ. (2021) 30:396–403. doi: 10.1016/j.hlc.2020.06.017
103. Ponikowski, P, Voors, AA, Anker, SD, Bueno, H, Cleland, JGF, Coats, AJS, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed). (2016) 69:1167. doi: 10.1016/j.rec.2016.11.005. Erratum in: Rev Esp Cardiol (Engl Ed). 2017; 70(4): 309-310. doi: 10.1016/j.rec.2017.02.027, 70, 309, 310
104. Kwon, OC, Han, K, Chun, J, Kim, R, Hong, SW, Kim, JH, et al. Effects of immune-mediated inflammatory diseases on cardiovascular diseases in patients with type 2 diabetes: a nationwide population-based study. Sci Rep. (2022) 12:11548. doi: 10.1038/s41598-022-15436-8
105. Gremese, E, De Lorenzis, E, and Ferraccioli, GF. Statins and mortality in connective tissue diseases: should we resume the cardio-rheumatology spirit in our clinics? J Rheumatol. (2018) 45:1617–9. doi: 10.3899/jrheum.180732
106. Redfield, MM, and Borlaug, BA. Heart failure with preserved ejection fraction: a review. JAMA. (2023) 329:827–38. doi: 10.1001/jama.2023.2020
Glossary
HFpEF - Heart Failure with Preserved Ejection Fraction
HFrEF - Heart Failure with Reduced Ejection Fraction
LVEF - Left Ventricular Ejection Fraction
LV - Left Ventricle
DD - Diastolic Dysfunction
ED - Endothelial Dysfunction
IL-6 - Interleukin-6
CRP - C-reactive Protein
RA - Rheumatoid Arthritis
SLE - Systemic Lupus Erythematosus
SSc - Systemic Sclerosis
APS - Anti-Phospholipid Syndrome
FMD - Flow-Mediated Dilation
ECM - Extracellular Matrix
TGF-β - Transforming Growth Factor Beta
NF-κB - Nuclear Factor Kappa-light-chain-enhancer of activated B cells
AP-1 - Activator Protein 1
ROS - Reactive Oxygen Species
eNOS - Endothelial Nitric Oxide Synthase
NO - Nitric Oxide
α-SMA - Alpha Smooth Muscle Actin
CCR2 - C-C Chemokine Receptor Type 2
STAT3 - Signal Transducer and Activator of Transcription 3
AMI - Acute Myocardial Infarction
DM2 - Type 2 Diabetes Mellitus
hsCRP - High Sensitivity C-Reactive Protein
MACE - Major Adverse Cardiovascular Events
BNP - B-type Natriuretic Peptide
NT-proBNP - N-terminal pro B-type Natriuretic Peptide
TNF - Tumor Necrosis Factor
OSM - Oncostatin M
BITE - Bispecific T-cell Engager
FDR - False Discovery Rate
WHS - Women’s Health Study
PMR - Polymyalgia Rheumatica
UC - Ulcerative Colitis
IBD - Inflammatory Bowel Disease
CFR - Coronary Flow Reserve
Keywords: inflammation, autoimmunity, endothelial dysfunction, diastolic dysfunction, heart failure with preserved ejection fraction
Citation: Gremese E, Bruno D, Perniola S, Ceolan J and Ferraccioli G (2025) Autoimmune inflammation as a key risk factor for heart failure with preserved ejection fraction: the different types of inflammation driving to HFpEF. Front. Med. 12:1557312. doi: 10.3389/fmed.2025.1557312
Edited by:
Konstantinos Triantafyllias, Rheumatology Center Rhineland Palatinate, GermanyReviewed by:
Changjiang Yu, Harbin Medical University Cancer Hospital, ChinaUmesh Bhattarai, University of Mississippi Medical Center, United States
Copyright © 2025 Gremese, Bruno, Perniola, Ceolan and Ferraccioli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Elisa Gremese, ZWxpc2EuZ3JlbWVzZUBodW5pbWVkLmV1; Z2ZmMTk5MEBnbWFpbC5jb20=
†ORCID: Elisa Gremese, orcid.org/0000-0002-2248-1058
Dario Bruno, orcid.org/0000-0002-6647-9208
Simone Perniola, orcid.org/0000-0001-6918-4731
Gianfranco Ferraccioli, orcid.org/0000-0002-6884-4301