Abstract
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 | |
|---|---|
| GOTO-KAKIZAKI Diabetes rat model (Insulin deficient- increased PKC and ROCK activity- Cardiomyocyte stiffening) (11, 12) |
Diastolic dysfunction precedes endothelium dysfunction |
| SAU-NA Hypertensive mouse model (unilateral nephrectomy, chronic exposure to aldosterone and accelerated mortality—hypertensive model—increased recruitment of macrophages CCR2+) (23) |
Diastolic dysfunction followed by cardiomyopathy and accelerated mortality |
| AGING Mouse model (increase in left ventricular mass, interstitial fibrosis, with high expression of TGFb and IL10 and CCR2 + macrophages) (24) |
Diastolic dysfunction, cardiomyocites hypertrophy and stiffness, microvascular dysfunction |
| Human phenotypes (age as the major risk factor) | |
|---|---|
| DIABETES (pathophysiologic mechanisms: alteration in sodium handling; increased volume overload; release of pro-inflammatory cytokines; endothelial and diastolic dysfunction) (32) | 45% of HFpEF have diabetes |
| OBESITY (pathophysiologic mechanisms: volume overload; endothelial and diastolic dysfunction; biventricular remodeling; impaired pulmonary vasodilation; systemic inflammation) (33) | 80% of HFpEF in US are obese |
| ATRIAL FIBRILLATION and FLUTTER (pathophysiologic mechanisms: widespread endothelial dysfunction; oxidative stress; microvascular inflammation with increased CRP levels; atrial and ventricular fibrosis) (35) | 40–60% of HFpEF have atrial fibrillation or flutter |
| HYPERTENSION (pathophysiologic mechanisms: coronary microvascular endothelial dysfunction; increased afterload on left ventricle; ventricular hypertrophy; diastolic dysfunction; systemic inflammation) (37) | 55% of patients with HFpEF have hypertension |
| CHRONIC RENAL DISEASES (pathophysiologic mechanisms: endothelial dysfunction, inflammation and systemic and renal fibrosis are mutual consequences of diabetes, hypertension and dyslipidaemia, which can also be drivers of cardiorenal syndrome) (40) | HFpEF patients: 26–49% have renal disease |
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:
-
RA: impaired response to acetylcholine, reversible with TNF-α blockade; long-term improvement requires disease remission (59, 60).
-
SSc: ED reversible with endothelin A receptor antagonism, but not with nitroprusside (61).
-
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.
Table 2
| Study | Disease | Key findings | Notable observations |
|---|---|---|---|
| Davis et al. (69) | RA | 35% 1-year mortality after HF vs. 19% in controls | High mortality burden in RA-related HF |
| Huang et al. (70) | RA | 8.2% developed HF over 10.7 years | Long-term CV risk in RA |
| Mantel et al. (71) | RA | 2.5% HF incidence over 5 years | Modest but relevant incidence |
| Myasoedova et al. (72) | RA | Stable HF prevalence over 30 years | Persistent CV burden despite treatment evolution |
| Ahlers et al. (73) | RA | HF incidence: 4.87 vs. 3.96 per 1,000 person-years | Higher chronic inflammatory load linked to HF |
| Athero-APS Study (74) | APS/SLE | HFpEF prevalence: 6.3% (carriers) to 27.8% (SLE-APS) | Severity-dependent CV risk escalation |
| Prasada et al. (75) | SSc, SLE, RA | HR for HF: 7.26 (SSc), 3.15 (SLE), 1.39 (RA) | Significant HF risk across diseases |
| Nomigolzar et al. (76) | SLE | 0.61% of 10 M HF cases had SLE; higher in-hospital mortality | Increased pericardial complications |
| Oliveira et al. (77) | SSc | 27% met HFpEF criteria | Age, AF, and ILD were key predictors |
| Rivera et al. (78) | ACIDs | 70.5% with HF had HFpEF | Higher rate than general population |
| Tada et al. (79) | ACIDs | 3x increased risk of death/hospitalization in HFpEF with ACID | Poorer prognosis vs. non-ACID patients |
Clinical evidence of HFpEF in autoimmune diseases.
RA, rheumatoid arthritis; APS/SLE, antiphospholipid syndrome/systemic lupus erythematosus; SSc, systemic sclerosis; ACIDs, autoimmune and chronic inflammatory diseases; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; AF, atrial fibrillation; ILD, interstitial lung disease.
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
| Clinical variables | Points |
|---|---|
| Weight (BMI > 30) | 2 |
| Hypertension (antihypertensive medications) | 1 |
| Atrial fibrillation (history or presence) | 3 |
| Pulmonary hypertension (RVSP at rest >35 mmHg) | 1 |
| Age (age >60 yrs) | 1 |
| Filling pressure (Rest E/e’ > 9) | 1 |
| Score 0–1 | Score 2–5 | Score 6–9 |
|---|---|---|
| HFpEF ruled out | HFpEF possible: assess rest/stress RHC or Echo stress | Very likely HFpEF |
H2FPEF score to evaluate the possible presence of HFpEF in patients with symptomatic dyspnea.
BMI, body mass index; RVSP, right ventricle systolic pressure; E/e’, ratio of early diastolic mitral inflow blood velocity to mitral annular tissue velocity; RHC, right heart catheterization.
Future research must focus on:
-
Longitudinal studies evaluating the impact of targeted anti-inflammatory therapies on HFpEF incidence across RA, SLE, and SSc.
-
Establishing evidence-based thresholds for biomarkers like NT-proBNP to guide routine screening.
-
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.
Statements
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
- 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
Glossary
References
1.
Andersson C 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Fonarow GC ADHERE 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Borlaug BA . Heart failure with preserved ejection fraction: a review. JAMA. (2023) 329:827–38. doi: 10.1001/jama.2023.2020
Summary
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
Received
08 January 2025
Accepted
28 July 2025
Published
15 October 2025
Volume
12 - 2025
Edited by
Konstantinos Triantafyllias, Rheumatology Center Rhineland Palatinate, Germany
Reviewed by
Changjiang Yu, Harbin Medical University Cancer Hospital, China
Umesh Bhattarai, University of Mississippi Medical Center, United States
Updates
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, elisa.gremese@hunimed.eu; gff1990@gmail.com
†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
Disclaimer
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.