Immunology of heart failure with preserved ejection fraction

Abstract

Introduction:

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by diastolic dysfunction, systemic comorbidities, and chronic low-grade inflammation. Emerging evidence suggests that immune dysregulation plays a central role in its pathophysiology. Both innate and adaptive immune responses contribute to myocardial remodeling, endothelial dysfunction, and comorbidity-driven inflammation that are hallmarks of HFpEF.

Areas covered:

In this systematic review, we summarize current evidence on the contribution of immunological pathways to HFpEF, including the role of proinflammatory cytokines, immune cell infiltration (particularly macrophages, mast cells, and T cells), and immune – endothelial interactions. We also highlight findings from experimental models linking systemic metabolic inflammation to myocardial fibrosis, coronary microvascular dysfunction, and cardiomyocyte stiffness in HFpEF. Finally, we explore potential immunomodulatory therapeutic approaches currently under investigation and discuss biomarkers of immune activation with potential clinical relevance.

Expert opinion:

While no immunologically targeted therapy is yet approved for HFpEF, interventions that modulate inflammation – such as IL-1 blockade, mast cell stabilization, or myeloid-targeted therapies – offer promise. Future clinical trials should incorporate immune profiling to enable patient stratification and personalized treatment approaches. A deeper understanding of immune-mediated mechanisms in HFpEF will be essential to advance therapeutic innovation and improve outcomes in this challenging and growing patient population.

1. Introduction

Heart failure (HF) with preserved ejection fraction (HFpEF) represents a complex clinical syndrome predominantly characterized by symptoms of HF alongside a left ventricular ejection fraction (LVEF) of 50% or greater. Historically, HFpEF was conceptualized as a form of HF that differed from HF with reduced ejection fraction (HFrEF), which is traditionally associated with systolic dysfunction. The recognition of HFpEF gained prominence in the late 20^th century as clinical studies began to reveal its growing prevalence – particularly among elderly populations and those with comorbidities such as hypertension and obesity [1,2]. As of now, HFpEF accounts for approximately half of all HF cases, shaping it into a critical public health issue across various demographics due to the associated morbidity and mortality risks [3,4].

2. HFpEF, HFpEF mimics, and secondary HFpEF

HFpEF presents a significant clinical challenge, characterized by a diastolic dysfunction wherein LVEF remains within normal limits (≥50%) despite the presence of symptoms related to HF [5]. Understanding its cellular and molecular mechanisms necessitates exploring a plethora of interrelated pathways that include immune dysregulation, systemic inflammation, endothelial dysfunction, metabolic alterations, and other comorbidities such as obesity and diabetes.

HFpEF mimics are conditions that present with clinical features similar to the ‘true’ HFpEF (e.g. dyspnea, fatigue, elevated natriuretic peptides, and preserved EF) but arise from different pathophysiologic processes. Unlike true HFpEF, these entities often have specific, potentially treatable causes and distinct structural or functional cardiac features. Another useful conceptual distinction in HFpEF is between primary and secondary forms. Primary HFpEF refers to cases where the HF phenotype arises as a direct result of intrinsic myocardial or microvascular alterations without a dominant external structural or systemic driver. These alterations include age-related myocardial fibrosis, hypertensive remodeling, obesity- and diabetes-induced cardiac changes, and microvascular inflammation. These cases are marked by a high burden of comorbidities (e.g. hypertension, obesity, insulin resistance, atrial fibrillation) that synergize to promote concentric hypertrophy, myocardial stiffness, impaired relaxation, and pulmonary hypertension. In contrast, secondary HFpEF arises due to distinct pathologies that indirectly cause a HFpEF phenotype.

Major examples include: i) Infiltrative cardiomyopathies: e.g. amyloidosis and sarcoidosis, which cause restrictive physiology and thickened ventricular walls, but with low voltage on ECG and extracardiac manifestations [6,7]; ii) storage disorders: e.g. Fabry disease, hemochromatosis, cause lysosomal or iron accumulation, respectively, leading to hypertrophy and conduction abnormalities [8,9]; iii) Constrictive pericarditis, which causes symptoms of right HF and elevated filling pressures due to impaired ventricular filling from a stiff pericardium [10]: imaging may show pericardial thickening or calcification, and ventricular interdependence is a key diagnostic clue [11]; iv) High-output HF: Conditions like anemia, hyperthyroidism, or arteriovenous fistulas can lead to symptoms of HF despite normal EF due to increased circulatory demand and volume overload [12]; v) Valvular heart disease, especially aortic stenosis and mitral regurgitation: in early or compensated stages, these conditions could preserve EF but lead to elevated filling pressures and HF symptoms [13]; vi) Pulmonary hypertension can cause dyspnea and right ventricular dysfunction, but is not primarily caused by LV diastolic dysfunction [14]. In clinical practice, distinguishing HFpEF from its mimics requires a careful and systematic diagnostic approach, which includes a detailed history (including red flag symptoms like neuropathy, proteinuria, or family history), ECG and imaging findings (e.g. cardiac MRI for infiltration or pericardial disease), and sometimes tissue biopsy or genetic testing. Misclassification can lead to inappropriate treatment – such as diuretics in amyloidosis or missed targeted therapies – emphasizing the importance of recognizing HFpEF mimics in the differential diagnosis of patients with preserved EF and HF symptoms.

The distinction between primary and secondary HFpEF has both diagnostic and therapeutic implications. Diagnostic workup should include echocardiography, cardiac MRI, and, in some cases, invasive hemodynamic assessment to characterize the underlying mechanism. Additionally, tissue biopsy or nuclear imaging may be necessary when infiltrative cardiomyopathy is suspected. Therapeutically, while primary HFpEF lacks universally effective disease-modifying therapies and often requires a multifaceted approach addressing volume status, comorbidities, and lifestyle, secondary HFpEF may benefit from etiology-specific interventions that alter the disease course. Therefore, the categorization into primary vs secondary HFpEF is essential for individualized patient care and underscores the importance of a precision medicine approach in this increasingly prevalent syndrome.

3. Cellular and molecular mechanisms underlying HFpEF – Immunology of HFpEF

HFpEF is increasingly recognized as a systemic syndrome driven by immune dysregulation. Herein, we discuss the main contribution to HFpEF of the various components of the immune response.

3.1. T cells

The adaptive immune system – particularly T lymphocytes – has emerged as a contributor to the complex inflammatory milieu of HFpEF (Table 1). Although HFpEF has historically been viewed as a disorder of diastolic mechanics driven by comorbidity-induced microvascular dysfunction and fibrosis, recent evidence indicates that adaptive immune dysregulation, including perturbations in T cell subsets and function, participates in disease pathogenesis and progression [15].

Table 1.

Main roles of T cells in HFpEF.

T Cell Subset	Phenotype/Markers	Role in HFpEF	Mechanisms	Relevant Evidence
CD4+ Th1 cells	IFN-γ+, T-bet+	Pro-inflammatory; contribute to myocardial remodeling and stiffness	Secrete IFN-γ, TNF-α → activate macrophages, promote fibrosis and endothelial dysfunction	Elevated in HFpEF patients and murine models; correlated with diastolic dysfunction
CD4+ Th2 cells	IL-4+, GATA3+	Ambiguous role; may modulate fibrosis	IL-4 may contribute to fibrosis by promoting alternative macrophage activation	Conflicting results; upregulated in some HFpEF contexts, especially with obesity
CD4+ Th17 cells	IL-17A+, RORγt+	Potent pro-inflammatory mediator in tissue inflammation and fibrosis	IL-17A promotes fibroblast activation, endothelial dysfunction, and neutrophil recruitment	Elevated in obese HFpEF models; associated with hypertension and increased ROS
Regulatory T cells (Tregs)	CD4+ CD25+ FoxP3+	Protective; counteract inflammation and fibrosis	Suppress effector T cell activity; promote tissue repair through IL-10 and TGF-β	Decreased function or numbers in HFpEF; augmentation improves outcomes in mouse models
CD8+ cytotoxic T cells	CD8+, perforin+, granzyme B+	Cytotoxic; contribute to cardiomyocyte apoptosis	Direct killing of stressed or antigen-presenting cardiomyocytes; release of cytotoxic granules	Accumulate in myocardium in some HFpEF models; implicated in diabetic and hypertensive HF
T follicular helper cells (Tfh)	CXCR5+ PD-1+ ICOS+	Support B cell responses; may contribute to autoimmunity	Enhance germinal center reactions; possible role in cardiac autoantibody production	Emerging evidence in autoimmune and fibrotic heart disease; not well studied in HFpEF
T resident memory cells (T_RM)	CD69+ CD103+	Long-lived tissue-resident; may perpetuate local inflammation	Remain in myocardium; quickly respond to local antigens or stress	Identified in inflamed cardiac tissue; may underlie recurrent inflammation in HFpEF
Senescent T cells (CD28−)	CD4+ or CD8+ CD28− CD57+	Senescence-associated pro-inflammatory (SASP) phenotype	Reduced proliferative capacity but secrete pro-inflammatory cytokines and contribute to fibrosis	Expanded in elderly and HFpEF patients; linked to systemic inflammation and comorbidities
MAIT cells	CD161+ Vα7.2+ (CD8+ or DN)	Mucosal-associated; modulate tissue inflammation	Recognize microbial antigens via MR1; secrete IFN-γ and IL-17 under stress	Reduced numbers but activated phenotype in HFpEF-like metabolic disease

Histological analyses of human endomyocardial biopsy specimens and animal models consistently demonstrate only modest infiltration of T lymphocytes in HFpEF myocardium, particularly when compared with macrophages [16]. In a chronic pressure-overload rat model of HFpEF, Sun and coworkers reported that CD3+ T cells were scarce in cardiac tissue even 24 weeks after surgery, whereas CD68+ macrophages predominated [16]. Similarly, mesoscopic profiling of murine HFpEF hearts showed focal clusters of immune cells with macrophages vastly outnumbering T lymphocytes, suggesting that local T cell – driven inflammation is limited or compartmentalized within the myocardium [17]. These observations raise the possibility that a systemic, rather than robust myocardial, T cell activation could underlie adaptive immune contributions to HFpEF. Although myocardial T cell infiltration is generally modest, systemic T cell activation – especially Th17 skewing – has been documented in HFpEF patients, potentially amplifying inflammation through IL-17 secretion [17]. Regulatory T cell (Treg) depletion exacerbates diastolic dysfunction and elevates proinflammatory cytokines in animal models, indicating a protective role for Tregs in restraining myocardial inflammation [18]. Aberrant complement activation, reflected by upregulated neutrophil CD55 expression, may further recruit immune cells and augment local inflammatory cascades [19]. These findings suggest that balancing effector and regulatory adaptive immune responses could modulate HFpEF progression. Most recently, Natural Killer T cells were shown to mediate the interorgan crosstalk between heart and brain in HFpEF [20].

Circulating T cell phenotypes in HFpEF patients reveal skewing toward proinflammatory effector subsets and concomitant perturbations in regulatory populations. An enrichment of Th17-like CD4+ T cells has been reported in the peripheral blood of HFpEF patients, accompanied by reduced frequencies of CD4+CD25+FoxP3+ regulatory T cells (Tregs); the Th17/Treg imbalance correlated with increased circulating levels of IL-17A, IL-6, and soluble ST2, markers linked to diastolic dysfunction and adverse prognosis [17]. This systemic T cell dysregulation may serve both as a biomarker and as a mechanistic driver of endothelial activation, microvascular inflammation, and fibrotic remodeling characteristic of HFpEF.

Th17 cells, through IL-17A secretion, can further amplify neutrophil recruitment and endothelial permeability, thereby potentiating a feed-forward cycle of inflammation and microvascular injury in HFpEF. Although originally characterized in mucosal immunity, Th17 cells have been detected in circulation during HFpEF and are posited to foster cardiac fibroblast activation via IL-17–mediated signaling pathways. In contrast, Tregs exert anti-inflammatory and antifibrotic effects by secreting IL-10 and transforming growth factor-β (TGF-β) and by modulating myeloid cell phenotypes. Experimental depletion of Tregs in a murine HFpEF model exacerbated diastolic dysfunction, increased cardiac IL-1β and tumor necrosis factor-α (TNF-α) expression, and promoted collagen deposition, underscoring a protective role for regulatory T cells in HFpEF [17].

The relative paucity of myocardial T cell infiltration in HFpEF suggests that T cell – mediated effects are exerted predominantly via paracrine mechanisms and systemic immunomodulation rather than direct cytotoxicity. Circulating Th17-driven cytokines such as IL-17A and IL-21 can modulate endothelial cell adhesion molecule expression (e.g. ICAM-1, VCAM-1), facilitating neutrophil and monocyte margination in the coronary microvasculature [17]. Concurrently, loss of Treg-derived IL-10 could disinhibit macrophage pro-fibrotic polarization (e.g. M2 phenotype), promoting extracellular matrix accumulation and ventricular stiffening [16]. Thus, the Th17/Treg axis constitutes a regulatory nexus linking adaptive immunity to the innate and stromal cell mediators of HFpEF.

Neutrophils and their extracellular traps (NETs) provide a critical link between systemic inflammation and local myocardial injury in HFpEF. Elevated circulating neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) correlate with natriuretic peptide levels and hospitalization risk [21,22]. In mice, transient neutrophil arrest within myocardial capillaries impairs blood flow and induces local hypoxia, driving diastolic dysfunction [23,24]. NETosis, promoted by damage-associated molecular patterns such as HMGB1, contributes to interstitial fibrosis, macrophage infiltration, and stiffness, while NET inhibitors (e.g. DNase I) restore diastolic function in experimental models [25]. Low-density neutrophils (LDNs), prone to NETosis and thrombogenic activity, are increased in HFpEF and correlate with IL-6, IL-8, and C-reactive protein (CRP), suggesting a hyperactivated phenotype that exacerbates microvascular inflammation [26].

Therapeutic strategies targeting T cell – mediated inflammation in HFpEF are in early preclinical stages but hold promise. IL-17 receptor antagonists and monoclonal antibodies against IL-17A (e.g. secukinumab) have demonstrated efficacy in other inflammatory diseases and may attenuate Th17-driven cardiac inflammation in HFpEF [17]. Approaches to expand the Treg compartment – such as low-dose IL-2 therapy – could restore immunological tolerance and suppress maladaptive fibrotic signaling. Moreover, antigen-specific tolerogenic vaccines or adoptive transfer of ex vivo – expanded Tregs offer potential for precise immunomodulation of the Th17/Treg imbalance. Elucidating cardiac autoantigens and T cell receptor repertoires in HFpEF could further refine these interventions.

So, although T cells infiltrate HFpEF myocardium only sparsely, systemic T cell dysregulation – manifest as Th17/Treg imbalance – contributes to endothelial activation, microvascular inflammation, and fibrotic remodeling in HFpEF. Proinflammatory Th17 cells amplify neutrophil and macrophage recruitment, while deficient Treg activity permits unchecked fibrosis. Targeting the Th17/Treg axis thus represents a novel immunotherapeutic avenue in HFpEF, warranting further mechanistic and translational investigation. Integrating T cell – centric biomarkers with existing clinical and imaging parameters may enable precision phenotyping and guide adaptive trial designs for immunomodulatory therapies in HFpEF.

3.2. B cells

B-cells constitute a key arm of the adaptive immune system, yet their contribution to HFpEF remains not fully defined (Table 2). HFpEF is increasingly recognized as a systemic inflammatory syndrome in which innate and adaptive immune mechanisms synergize to promote endothelial dysfunction, microvascular inflammation, and myocardial fibrosis. B cells shape immune responses through antibody production, antigen presentation, and cytokine secretion. In other forms of HF, autoreactive B cells generate anti-cardiac antibodies that exacerbate myocardial injury and remodeling [27,28]. B-cell – derived immunoglobulins can activate complement on endothelial surfaces, promoting leukocyte recruitment and microvascular damage [21]. Moreover, B cells express co-sti-mulatory molecules (e.g. CD80/86) that modulate T-cell responses, potentially amplifying pathogenic Th17 activation [5]. These paradigms suggest plausible roles for B cells in HFpEF, although direct evidence in this syndrome is absent. Clinical HFpEF cohorts exhibit elevated complement activation fragments and dysregulated complement regulators such as CD55 on neutrophils, indicative of systemic complement engagement [19]. Since complement fixation is driven primarily by immunoglobulin binding, B-cell – derived autoantibodies might initiate or perpetuate microvascular inflammation in HFpEF [19,29]. Assessing circulating anti-cardiac autoantibodies and complement split products (C3a, C5a) in HFpEF patients could clarify whether B cells contribute to endothelial dysfunction and diastolic stiffness.

Table 2.

Functional contribution of B cells in HFpEF.

B Cell Subset	Phenotype/Markers	Role in HFpEF	Mechanisms	Relevant Evidence
Naive B cells	IgD+ CD27−	Limited direct involvement; potential source of antigen-experienced clones	Can differentiate into memory or plasma cells upon activation	Altered proportions reported in HFpEF and aging-associated immune profiles
Memory B cells	CD27+ IgG+ or IgA+	Antigen-experienced; may drive persistent inflammation or autoantibody production	Provide rapid secondary responses; involved in T cell – B cell crosstalk and cytokine production	Expanded in metabolic syndrome; associated with inflammatory B cell phenotype in HFpEF
Plasma cells	CD138+ CD38+	Antibody-secreting; may produce pathogenic autoantibodies	Autoantibodies against cardiac antigens may drive myocardial injury or endothelial activation	Autoantibody signatures detected in HFpEF-like models; role in fibrosis under investigation
Regulatory B cells (Bregs)	CD19+ CD24^iCD38^hi or CD5+ CD1d+	Protective; produce anti-inflammatory cytokines	Secrete IL-10 and TGF-β to suppress T cell and macrophage activation	Decreased in HFpEF and aging; restoration improves immune balance in preclinical models
Age-associated B cells (ABCs)	CD11c+ T-bet+	Pro-inflammatory; linked to senescence and metabolic inflammation	Secrete TNF-α, IL-6; express high levels of TLRs; antigen presentation to T cells	Expanded in obesity, diabetes, and aging – all HFpEF risk factors
Marginal zone-like B cells	CD21^lowCD23−	Innate-like rapid responders; role unclear in HFpEF	Respond quickly to blood-borne antigens; may influence early inflammatory tone	Enriched in inflammatory states; limited data in HFpEF
B1 cells	CD5+ (in mice; not clearly defined in humans)	Natural antibody producers; role in tissue homeostasis	Produce IgM with low affinity to self-antigens; may modulate clearance of apoptotic cells	Altered proportions in obesity and metabolic syndrome
Tertiary lymphoid structure (TLS)-associated B cells	Mixed (germinal center phenotype)	May support chronic inflammation in myocardium or vasculature	Local antigen presentation, autoantibody generation, and cytokine signaling	TLSs identified in cardiac and perivascular tissues in chronic heart conditions

Beyond antibodies, B cells secrete cytokines – such as IL-6, TNF-α, lymphotoxin, and B-cell activating factor (BAFF) – that modulate myeloid and stromal cell behavior [21]. IL-6, a B-cell growth factor, is elevated in HFpEF and linked to titin hypophosphorylation and increased myocardial stiffness [30]. BAFF and APRIL regulate B-cell survival and have been implicated in vascular inflammation and remodeling in hypertension models [21]. Investigating B-cell cytokine expression in HFpEF may uncover novel pathways driving microvascular rarefaction and fibrosis. Endomyocardial biopsies from HFpEF patients have not yet been systematically evaluated for B-cell markers (e.g. CD19, CD20, CD138). In pressure-overload and SAUNA murine HFpEF models, infiltrating leukocytes are overwhelmingly macrophages, with negligible T-cell and neutrophil presence after chronic injury [16]. No data are available on B-cell homing to the HFpEF myocardium. Immunohistochemical and flow-cytometric studies are therefore warranted to determine whether B cells infiltrate cardiac tissue or reside in perivascular niches in HFpEF. Noninvasive biomarkers – including serum immunoglobulin isotypes, BAFF levels, —could serve as surrogates of B-cell activation in HFpEF. Proteomic profiling in HFpEF has identified acute-phase and remodeling proteins but did not detect immunoglobulin-related signatures, likely reflecting a focus on abundant plasma proteins [31,32]. Molecular imaging modalities, such as PET tracers targeting CD20 or Fc receptors, may permit in vivo visualization of B-cell accumulation in the HFpEF heart [33]. Integration of these biomarkers with machine-learning diagnostic models could reveal B-cell – driven HFpEF phenotypes [34]. If B cells are found to promote HFpEF pathogenesis, anti-B-cell therapies might be repurposed for HFpEF. Rituximab (anti-CD20) has demonstrated efficacy in autoimmune cardiac syndromes and could mitigate autoantibody-mediated endothelial injury [21]. Alternatively, BAFF inhibitors (e.g. belimumab) may suppress pathogenic B-cell survival and cytokine release. Immunoadsorption of circulating IgG has shown benefits in dilated cardiomyopathy but remains untested in HFpEF [29]. Early-phase trials employing B-cell – targeted agents, guided by biomarker endpoints, would clarify the therapeutic potential of B-cell modulation in HFpEF. B cells are central to adaptive immunity in cardiovascular disease but remain unexplored in HFpEF. The paucity of data on B-cell phenotypes, myocardial infiltration, and antibody-mediated mechanisms represents a major gap. Given the systemic inflammatory milieu of HFpEF, it is plausible that B-cell – driven autoimmunity and cytokine production contribute to endothelial dysfunction and fibrotic remodeling [35]. Rigorous clinical and preclinical investigations – encompassing immunophenotyping, tissue analyses, biomarker discovery, and molecular imaging – are urgently needed to define the role of B cells in HFpEF and to identify novel immunomodulatory strategies.

3.3. Monocytes and macrophages

Patients with HFpEF exhibit elevated circulating monocyte counts and increased monocyte-to-lymphocyte ratios, reflecting systemic immune activation. In a mouse model of HFpEF induced by diet and nitric oxide (NO) synthase inhibition, Ly6Chi (‘classical’) monocytes were selectively mobilized from bone marrow and spleen and infiltrated the heart early in disease [36]. Human HFpEF cohorts similarly demonstrate elevated serum levels of monocyte-derived cytokines (e.g. IL-6, TNF-α) correlating with worse diastolic indices and right-sided pressures [37]. Single-cell RNA sequencing in a dyslipidemia-induced model of diastolic dysfunction revealed that metabolic stress preferentially activates a CD14+CD16+ intermediate monocyte subset with a proinflammatory transcriptome, including upregulation of TNF, IL1B, and matrix-remodeling genes [37].

The healthy heart contains embryonically derived, self-renewing macrophages, but HFpEF is characterized by the recruitment of circulating monocyte-derived macrophages. Both the proteolytic and the profibrotic macrophage subsets have been shown to accumulate in murine HFpEF myocardium, secreting IL-10 and TGF-β that drive collagen cross-linking and impair relaxation [38]. Monocyte recruitment via CXCR4 and subsequent macrophage-to-fibroblast paracrine signaling have been shown to be essential for fibrotic remodeling in a hypertensive HFpEF model [39]. Genetic or pharmacologic blockade of CXCR4 reduced macrophage infiltration, attenuated fibroblast activation, and improved diastolic stiffness [39].

Monocyte-derived macrophages infiltrate the HFpEF myocardium, with CD68+ cell densities elevated in human endomyocardial biopsies and animal models [40,41]. Macrophage polarization skews toward M2-like, pro-fibrotic phenotypes in chronic pressure-overload models, releasing TGF-β and other cytokines that stimulate fibroblast activation and interstitial collagen deposition [16]. CXCR4-mediated monocyte recruitment amplifies macrophage-to-fibroblast signaling, aggravating diastolic dysfunction; pharmacologic CXCR4 antagonists have been shown to attenuate fibrosis and improve ventricular stiffness in murine HFpEF [39]. Additionally, myeloid-cell – derived IL-1β contributes to pulmonary vascular remodeling and right ventricular dysfunction, highlighting the heart – lung inflammatory axis in HFpEF [42].

In dyslipidemia models, cardiac macrophages upregulated glycolytic and lipid-handling pathways under metabolic stress, promoting proinflammatory polarization [37]. This metabolic switch may link systemic comorbidities – such as obesity and diabetes – to myocardial immune activation. Agents that correct macrophage metabolic dysfunction – such as sodiumglucose cotransporter 2 (SGLT2) inhibitors – reduce cardiac macrophage numbers and inflammatory cytokine expression in HFpEF models, potentially by limiting substrate availability for proinflammatory polarization [43].

Recruited macrophages secrete IL-1β, IL-6, and matrix metalloproteinases (MMPs) that degrade extracellular matrix and stimulate myofibroblast differentiation; concurrent IL-10 production by MHC-IIlo macrophages paradoxically enhances collagen cross-linking through lysyl oxidase (LOX) upregulation, further increasing myocardial stiffness [38].

Although predominantly studied in ischemic and pressure-overload contexts, disruption of STAT6 signaling in myeloid cells promotes profibrotic macrophage activation and cardiac fibrosis, suggesting that impaired M2-like responses may exacerbate HFpEF remodeling [44]. CXCR4 inhibitors (e.g. plerixafor) attenuate monocyte trafficking and have shown preclinical efficacy in reducing fibrosis and improving relaxation [39]. Neutralizing antibodies against IL-1β and IL-6 might impede macrophage-driven inflammation, although definitive clinical data in HFpEF are not available. Enhancing IL-10 signaling represents an alternative to skew macrophages toward a reparative phenotype. The main roles of monocyte/macrophages in HFpEF are summarized in Table 3. Key gaps remain in mapping the temporal dynamics and spatial localization of monocyte-derived versus resident cardiac macrophages in HFpEF. Advanced imaging (e.g. PET tracers for translocator protein) could noninvasively quantify macrophage burden and monitor responses to anti-inflammatory therapies. Single-cell and spatial transcriptomic profiling of human HFpEF biopsies will be critical to identify disease-specific macrophage subsets and validate targets. Integration of monocyte/macrophage biomarkers into HFpEF phenotyping might enable patient stratification for immunomodulatory trials.

Table 3.

Roles of monocyte–macrophage lineage in HFpEF.

Subset/Type	Phenotype/Markers	Role in HFpEF	Mechanisms	Relevant Evidence
Classical monocytes	CD14+ + CD16− (human); Ly6^hi (mouse)	Pro-inflammatory; recruited to tissues during stress	Produce TNF-α, IL-1β, and MCP-1; differentiate into inflammatory macrophages in cardiac tissue	Expanded in HFpEF; associated with comorbidities (e.g. obesity, hypertension)
Intermediate monocytes	CD14+ CD16+	Bridge between classical and non-classical monocytes	Secrete both pro- and anti-inflammatory cytokines; potent antigen presentation	Increased proportions correlate with vascular inflammation and endothelial activation
Non-classical monocytes	CD14^dimCD16+ (human); Ly6^lo (mouse)	Patrolling; may promote resolution or chronic inflammation	Survey endothelium; secrete IL-10 and scavenge debris	Altered function in aging and metabolic syndrome – key features of HFpEF
Pro-inflammatory (M1-like)	CD68+ CD80+ CD86+ iNOS+	Amplify tissue inflammation and fibrosis	Produce IL-1β, IL-6, and reactive oxygen species (ROS); activate fibroblasts	Enriched in myocardium and perivascular fat in HFpEF models
Anti-inflammatory (M2-like)	CD206+ CD163+ Arg1+	Involved in tissue repair and fibrosis resolution	Secrete IL-10 and TGF-β; support angiogenesis and extracellular matrix turnover	Impaired M2 polarization reported in metabolic HFpEF; imbalance favors chronic inflammation
Tissue-resident macrophages	CX3CR1+ Timd4+ (mouse); CD64+ CD11b^int (human)	Maintain local homeostasis; modulate immune responses	Clear apoptotic cells, regulate local inflammation, support endothelial barrier	Depleted or functionally impaired in aging and diabetic HFpEF hearts
Cardiac infiltrating macrophages	CD11b+ F4/80+ MHC-II+ (mouse)	Drive myocardial remodeling and diastolic dysfunction	Secrete cytokines, matrix metalloproteinases (MMPs), and fibrotic factors	Central to perivascular inflammation and fibrosis in HFpEF models
Perivascular macrophages	CD11b+ F4/80+ CD206+ in perivascular niches	Modulate vascular stiffness and endothelial dysfunction	Crosstalk with vascular smooth muscle cells; secrete TGF-β and PDGF	Observed in coronary microvascular inflammation in HFpEF human and mouse studies
Macrophage-derived foam cells	CD36+ CD68+ (in metabolic disease)	Promote oxidative stress and stiffening	Lipid accumulation; secrete pro-oxidant and pro-inflammatory mediators	Seen in obese/diabetic HFpEF models; link to endothelial and mitochondrial dysfunction

3.4. Mast cells

Mast cells play an increasingly recognized role in the pathophysiology of HFpEF (Table 4), primarily through their contribution to inflammation, microvascular dysfunction, and myocardial fibrosis – hallmarks of this condition (as detailed in the sections below).

Table 4.

Fundamental roles of mast cells in HFpEF.

Subset/Type	Phenotype/Markers	Role in HFpEF	Mechanisms	Relevant Evidence
Connective tissue-type mast cells (CTMCs)	CD117+ (c-Kit), FcεRI+, tryptase+, chymase+	Promote myocardial and perivascular fibrosis	Release chymase, tryptase, and histamine; activate fibroblasts and TGF-β signaling	Increased in perivascular spaces of HFpEF hearts; chymase promotes collagen deposition
Mucosal-type mast cells (MMCs)	CD117+, tryptase+, low or absent chymase	Less abundant in myocardium	May contribute to systemic inflammation and vascular permeability	Rare in cardiac tissue; limited evidence in HFpEF
Activated degranulating mast cells	Degranulation visualized by tryptase staining or EM	Initiate acute and chronic inflammatory cascades	Release histamine, cytokines (e.g. IL-6, TNF-α), leukotrienes, and proteases	Degranulation observed in myocardial biopsies and animal models of HFpEF
Perivascular mast cells	Tryptase+, localized to adventitia or periarteriolar regions	Contribute to microvascular rarefaction and stiffness	Promote endothelial dysfunction, ROS generation, and smooth muscle proliferation	Enriched in coronary microcirculation of HFpEF patients
Chymase-producing mast cells	Chymase+ (serine protease)	Facilitate cardiac remodeling and fibrosis	Activate TGF-β, angiotensin II, and MMPs; potentiate extracellular matrix deposition	Pharmacologic inhibition of chymase reduces HFpEF-like features in animal models
Tryptase-producing mast cells	Tryptase+	Promote inflammation and matrix degradation	Activate PAR-2, stimulate fibroblasts, and recruit other immune cells	Elevated tryptase levels correlate with diastolic dysfunction severity
Histamine-releasing mast cells	Release histamine upon IgE or non-IgE triggers	Modulate vascular tone, permeability, and inflammatory recruitment	Induce vasodilation and endothelial activation; may impair coronary reserve	Histamine implicated in myocardial and vascular remodeling in HFpEF comorbid contexts

In HFpEF, systemic comorbidities such as hypertension, obesity, and diabetes drive chronic low-grade inflammation; mast cells, which are resident in cardiac tissue and abundant in perivascular regions, become activated in this inflammatory milieu [45]. Upon activation, they degranulate and release a variety of pro-inflammatory and pro-fibrotic mediators, including histamine, tryptase, chymase, TNF-α, and interleukins [46,47]. These factors amplify local inflammation and recruit additional immune cells, sustaining the inflammatory cascade.

HFpEF is characterized by coronary microvascular rarefaction and endothelial dysfunction, which impair NO bioavailability and lead to increased cardiomyocyte stiffness. Mast cell-derived mediators – particularly histamine and chymase – can contribute to endothelial activation and permeability, exacerbating capillary leak, promoting leukocyte adhesion, and impairing vasodilation [48]. Chymase can also convert angiotensin I to angiotensin II independently of ACE [49], further promoting vasoconstriction and inflammation.

Mast cells are potent sources of fibrogenic signals, such as TGF-β, platelet-derived growth factor (PDGF), and tryptase [50,51], which activate cardiac fibroblasts and stimulate extracellular matrix production. The resulting interstitial fibrosis contributes to myocardial stiffening – a central mechanism of diastolic dysfunction in HFpEF.

Preclinical studies in models of pressure overload and metabolic stress have shown increased cardiac mast cell infiltration and that mast cell stabilization (e.g. with cromolyn sodium) can reduce fibrosis and improve diastolic function [52–54]. Clinical studies have also reported elevated mast cell density and tryptase expression in myocardial biopsies from HFpEF patients [55], supporting their relevance in human disease. These findings suggest that targeting mast cell activation or specific mast cell-derived mediators may represent a novel therapeutic strategy in HFpEF.

4. Inflammation and HFpEF: roles of specific cytokines

Chronic low-grade inflammation emerges as a major contributor to the pathophysiology of HFpEF. Systemic inflammatory markers, including cytokines such as TNF-α and interleukins (e.g. IL-1β and IL-6), are often elevated in HFpEF patients, reflecting ongoing systemic immune activation and correlating with diastolic dysfunction severity [18,19,56,57]. These pro-inflammatory mediators can drive myocardial fibrosis, impair endothelial function, and exacerbate diastolic dysfunction [32,58,59]. In particular, TNF-α is known to activate various inflammatory pathways, contributing to increased vascular permeability and cardiomyocyte stress [57,60].

HFpEF predominantly affects older individuals burdened with multiple noncardiac comorbidities whose chronic low-grade inflammation is hypothesized to trigger coronary micro-vascular endothelial dysfunction [21,61]. In this context, comorbidity-derived cytokines penetrate the myocardial interstitium, where they impair NO bioavailability and cyclic guanosine monophosphate (cGMP)-dependent protein kinase G (PKG) signaling in cardiomyocytes, leading to increased resting tension, hypertrophy, and interstitial fibrosis [21]. Preclinical models of HFpEF induced by combined metabolic (high-fat diet) and renal stress recapitulate elevated plasma levels of IL-6 and TNF-α, and demonstrate that neutralization of these cytokines ameliorates both diastolic dysfunction and myocardial relaxation kinetics. These findings underscore the mechanistic plausibility of a systemic-to-microvascular-to-myocardial inflammatory axis in HFpEF.

Among the pro-inflammatory cytokines, IL-6 has garnered particular attention due to its consistent association with incident HFpEF and adverse outcomes. In community-based cohorts, elevated baseline IL-6 predicted future HFpEF development independently of traditional cardiovascular risk factors, while in HFpEF patients, higher IL-6 concentrations correlated with increased rates of cardiovascular mortality and rehospitalization [62–65]. Mechanistically, IL-6 fosters fibroblast-to-myofibroblast transformation and collagen deposition in the myocardium and exacerbates arterial stiffness by promoting endothelial dysfunction and vascular smooth muscle cell proliferation [21,64]. Furthermore, IL-6 amplifies local inflammation via trans-signaling pathways, thereby sustaining a feed-forward loop of tissue injury and reparative fibrosis that impairs ventricular compliance [63].

TNF-α, another potent pro-inflammatory cytokine, has been implicated in HFpEF pathobiology through multiple lines of evidence. HFpEF patients exhibit elevated circulating TNF-α levels compared to controls, and mechanistic studies demonstrate that TNF-α impairs calcium handling in cardiomyocytes and reduces titin phosphorylation, thereby increasing passive stiffness. Interestingly, receptor-level analyses reveal that TNF-α receptor 2 is disproportionately upregulated in HFpEF relative to HFrEF, suggesting distinct receptor-mediated signaling profiles across HF phenotypes. Experimental neutralization of TNF-α in animal HFpEF models restores myocardial relaxation and mitigates perivascular fibrosis, further supporting a causal role.

IL-1β and related family members participate in the initiation and amplification of sterile inflammation and have been detected at higher levels in HFpEF patients versus both HFrEF and non-HF controls [66]. Activation of the NLRP3 inflamma-some in immune cells and cardiac fibroblasts leads to IL-1β release, which in turn upregulates adhesion molecules, chemokines, and additional cytokines, thus recruiting monocytes and perpetuating interstitial inflammation and fibrosis [21]. Although clinical data specific to IL-1 blockade in HFpEF remain limited, small proof-of-concept studies using IL-1 receptor antagonists demonstrate improved exercise capacity and reduced natriuretic peptide levels, highlighting the therapeutic promise of this axis [67–69].

Monocyte Chemoattractant Protein-1 (MCP-1, CCL2) drives monocyte recruitment into the myocardium and is elevated in HFpEF, particularly in obese and diabetic phenotypes [65,70]. Once infiltrated, monocytes differentiate into macrophages, whose phenotypic polarization (M1 vs. M2) dictates local cytokine profiles: M1 macrophages secrete pro-inflammatory mediators (e.g. IL-6, TNF-α), whereas M2 macrophages produce TGF-β and facilitate fibrosis [70]. Dysregulated macrophage polarization therefore contributes to a maladaptive reparative response characterized by excessive extracellular matrix deposition and increased myocardial stiffness. Epicardial adipose tissue (EAT), which envelops the myocardium, represents a rich source of biologically active cytokines and adipokines that can modulate myocardial structure and function [70]. In HFpEF patients, EAT thickness correlates positively with plasma IL-6, C-reactive protein, and uric acid levels, and associates with worse hemodynamic compromise and exercise intolerance [71]. Adipocyte-derived IL-6 and MCP-1 facilitate local inflammatory cell infiltration into the adjacent myocardium, thereby amplifying microvascular dysfunction and perivascular fibrosis [70].

Multiplex analyses in large HF cohorts reveal that inflammation-related biomarkers (e.g. IL-6, TNF-α, pentraxin-3, soluble suppression of tumorigenicity-2) display stronger associations with HFpEF compared to HFrEF and improve risk stratification beyond natriuretic peptides alone. Network-based approaches identify clusters of cytokine-mediated pathways, including angiogenesis, immune activation, and extracellular matrix remodeling, as key discriminators of HFpEF phenotypes [71]. IL-6 in particular emerges as a consistent predictor of both HFpEF onset in asymptomatic individuals and adverse clinical outcomes post-hospitalization [63,64].

Given the centrality of cytokine-driven inflammation in HFpEF (Table 5), several therapeutic strategies have been explored. Selective inhibition of IL-6 trans-signaling using monoclonal antibodies has shown promise in preclinical HFpEF models, improving diastolic function and reducing myocardial fibrosis [21,62]. Anti-TNF therapies, despite disappointing results in HFrEF, may warrant revisitation in HFpEF subsets with pronounced TNF-α signaling. Furthermore, agents targeting upstream inflammasome activation or macrophage polarization hold potential to modulate multiple cytokine pathways simultaneously [21].

Table 5.

Roles of cytokines in HFpEF.

Cytokine	Source Cells	Primary Role in HFpEF	Mechanisms	Clinical/Experimental Evidence
TNF-α	Macrophages, T cells, mast cells, adipocytes	Pro-inflammatory, promotes myocardial inflammation	Activates NF-κB pathway, promotes endothelial dysfunction and fibrosis	Elevated in HFpEF patients; associated with diastolic dysfunction
IL-6	Macrophages, T cells, endothelial cells	Systemic inflammation, myocardial hypertrophy	Induces STAT3 activation, promotes cardiomyocyte hypertrophy and fibrosis	Correlates with severity of HFpEF and systemic comorbidities
IL-1β	Monocytes/macrophages, endothelial cells	Induces endothelial activation and fibrosis	Activates inflammasomes, upregulates adhesion molecules and pro-fibrotic genes	Inhibition improves cardiac function in preclinical HFpEF models
TGF-β	Macrophages, fibroblasts, mast cells	Central driver of fibrosis and ECM remodeling	Stimulates fibroblast differentiation into myofibroblasts, increases collagen	Strongly upregulated in HFpEF; therapeutic target in animal models
IL-10	Regulatory T cells, M2 macrophages	Anti-inflammatory, protective effects	Suppresses pro-inflammatory cytokine production, inhibits macrophage activation	Decreased levels may contribute to immune imbalance in HFpEF
IL-17A	Th17 cells	Pro-inflammatory, promotes neutrophil recruitment	Stimulates IL-6 and TNF-α production, increases vascular permeability	Elevated in some HFpEF models; links immune activation to vascular injury
IFN-γ	Th1 cells, NK cells	Immune activation, promotes endothelial dysfunction	Induces ROS, impairs NO bioavailability, upregulates adhesion molecules	Correlated with impaired vasodilation in HFpEF patients
IL-4/IL-13	Th2 cells	Promotes fibrosis and alternative macrophage activation (M2)	Stimulate TGF-β signaling, eosinophil recruitment, and ECM production	Implicated in pro-fibrotic cardiac remodeling in HFpEF models
MCP-1 (CCL2)	Endothelial cells, fibroblasts, macrophages	Recruits monocytes/macrophages to myocardium	Binds CCR2 on monocytes; amplifies local inflammation and fibrosis	Elevated in HFpEF; MCP-1 inhibition reduces cardiac fibrosis in models
IL-33	Endothelial cells, fibroblasts	Dual role: pro-inflammatory and cardioprotective (context-dependent)	Activates ST2 pathway; can promote hypertrophy or limit inflammation	Soluble ST2 (sST2) elevated in HFpEF and used as a prognostic biomarker
GM-CSF	T cells, macrophages	Enhances antigen-presenting cell activity	Increases dendritic cell survival and inflammation	Suggested to contribute to immune activation in cardiometabolic HFpEF
IL-18	Macrophages, epithelial cells	Pro-inflammatory, inflammasome-related cytokine	Activates IFN-γ production, promotes vascular injury	Associated with coronary microvascular dysfunction in HFpEF patients
Osteopontin (OPN)	Macrophages, fibroblasts, cardiomyocytes	Pro-fibrotic and inflammatory signaling mediator	Enhances collagen deposition, fibroblast activation	Strongly upregulated in HFpEF myocardium; potential therapeutic target

Optimal management of HFpEF requires a multimodal approach that addresses both systemic comorbidities and myocardial inflammation. Weight reduction in obese HFpEF patients attenuates EAT volume and lowers circulating IL-6, improving exercise capacity [21]. Aggressive control of blood pressure and glycemia can mitigate cytokine production from vascular and renal sources, thereby preserving microvascular function and delaying HFpEF progression [21,72]

Despite compelling mechanistic and biomarker data, large-scale clinical trials of anti-inflammatory therapies in HFpEF remain scarce. Key challenges include patient heterogeneity, identification of inflammation-dominant phenotypes, and optimal timing of intervention. Integration of precision phenotyping – combining circulating cytokine profiles with imaging and genomics – may enable targeted therapy and improve trial success [73].

As previously discussed, pro-inflammatory cytokines such as TNF-α and IL-6 directly influence cardiomyocyte and fibroblast function. TNF-α promotes hypertrophy and extracellular matrix turnover, while IL-6 induces endothelial activation and leukocyte recruitment [30]. Chronic exposure to these cytokines leads to titin hypophosphorylation, increasing cardiomyocyte passive stiffness and exacerbating diastolic dysfunction; IL-6 receptor blockade has been shown to restore titin phosphorylation and compliance in experimental myocarditis [30]. Anti-cytokine therapies, including IL-1β and IL-6 antagonists, have yielded promising preclinical results but require rigorous clinical evaluation in HFpEF populations [42,74]. Alternative immunomodulatory strategies, such as vagus nerve stimulation, harness the cholinergic anti-inflammatory pathway to reduce myocardial inflammation and fibrosis through α7 nicotinic acetylcholine receptor – mediated effects on macrophages [75].

The role of macrophages in HFpEF has recently gained more attention, with studies indicating that M2 macrophage activation may drive cardiac fibrosis and inflammation, contributing to diastolic dysfunction [16,76]. The infiltration of immune cells into the myocardium exacerbates this inflammation, leading to structural and functional remodeling of the heart [77,78]. Recently, also intramyocardial lipotoxicity has been shown to contribute to cardiac dysfunction in HFpEF [79,80]. Circulating indices of inflammation, including neutro-phil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), are elevated in HFpEF patients and independently predict adverse outcomes [21,22,81]. Proteomic analyses have identified novel biomarkers such as lipocalin-2 (LCN2), which has been shown to correlate with prevalent HFpEF and underscores inflammation in disease pathogenesis [32].

Emerging anti-inflammatory therapies to treat HFpEF include myeloperoxidase (MPO) inhibitors (AZD4831, also known as mitiperstat) and chemokine receptor blockers targeting CXCR4 and CCR2 pathways [42,82]. MPO, predominantly released by degranulating neutrophils, binds to the subendothelial matrix, where its enzymatic activity propagates oxidative injury and diastolic dysfunction [74]. In the SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With HF) study, a double-blind randomized 3-month trial evaluating safety and tolerability of AZD4831 in HFpEF, the inhibition of MPO significantly downregulated several markers of inflammation, including CDCP1, PRELP, CX3CL1, LIFR, VSIG2 [83].

Early-phase trials of IL-6 receptor antagonists [84] and IL-1β inhibitors [85] in HFpEF are supported by preclinical data demonstrating reversal of titin hypophosphorylation and fibrosis [30,42,86]. Vagal neuromodulation represents a non-pharmacologic approach to immune modulation, with transcutaneous stimulation reducing myocardial macrophage infiltration and fibrosis in preclinical studies [75]. Adaptive trial designs incorporating early biomarker endpoints may accelerate the identification of responders and refine therapeutic algorithms.

Molecular imaging of cardiac inflammation via PET tracers targeting activated macrophages, neutrophils, and MPO provides noninvasive assessment of myocardial immune landscapes in HFpEF [33]. Such imaging modalities enable patient selection for targeted immunotherapies, real-time monitoring of treatment effects, and elucidation of in vivo mechanisms. Integration of imaging with serum biomarkers and multi-omic data will facilitate precision phenotyping and mechanism-guided therapy in HFpEF. Ongoing research is exploring anti-inflammatory approaches due to the involvement of systemic inflammation in the pathophysiology of HFpEF [87].

5. Endothelial dysfunction

Endothelial dysfunction undoubtedly represents a critical pathway in HFpEF, contributing to both microvascular and macro-vascular complications. Patients often exhibit impaired endothelial-dependent vasodilation, which can exacerbate hypertension – a common comorbidity in HFpEF patients [62]. Dysfunction in the endothelium leads to reduced NO bioavailability, promoting further cardiovascular alterations such as vascular stiffness and increased systemic vascular resistance. Furthermore, vascular inflammation and systemic endothelial dysfunction can lead to coronary microvascular dysfunction. Such microvascular impairments are particularly relevant in the context of obesity and diabetes, where insulin resistance further worsens endothelial performance [21,88]. Data suggest that microvascular dysfunction may be a more significant contributor to HFpEF than myocardial fibrosis itself [62].

Endothelial dysfunction in HFpEF mostly arises from oxidative stress – driven reduction of NO bioavailability and impaired endothelial NO synthase signaling, facilitating leukocyte adhesion, capillary rarefaction, and microvascular inflammation [30,89]. Activated endothelial cells upregulate adhesion molecules (e.g. VCAM-1, ICAM-1) and release pen-traxin-3, promoting immune cell recruitment to the myocardial interstitium [30,89]. Likewise, NADPH oxidase (NOX) isoform upregulation in microvascular cells amplifies reactive oxygen species (ROS) production, further compromising myocardial perfusion and compliance [90]. Cytokines such as IL-6 and TNF-α directly compromise endothelial barrier integrity, diminish NO bioavailability, and promote endothelial-to-mesenchymal transition, all of which contribute to capillary rarefaction and increased vascular stiffness. Intravascular imaging studies and perivascular fat attenuation on computed tomography link systemic cytokine elevations to objective indices of microvascular dysfunction in HFpEF patients, thereby validating the comorbidity – inflammation – microvasculature paradigm [91].

6. Fibrosis and metabolic dysfunction

Myocardial fibrosis is one of the most significant structural alterations observed in HFpEF. Fibroblast activation and collagen deposition are prominent features, driven by inflammatory stimuli and mechanical stress [75,92,93]. The expression of connective tissue growth factor (CTGF) and other profibrotic factors, such as TGF-β, has been implicated in fostering a fibrotic response that compromises diastolic function by enhancing myocardial stiffness [57]. Interestingly, several studies have reported that galectin-3 and other biomarkers could serve as indicators of ongoing fibrotic processes in patients suffering from HFpEF [62,94]. Notably, the inter-relationship of inflammation and fibrosis through cytokine signaling appears to constitute a vicious cycle that continues to undermine cardiac function [95].

At the cellular level, alterations in calcium handling, particularly through changes in sarcoplasmic reticulum function, also contribute to diastolic dysfunction exhibited in HFpEF. Proteins like titin, pivotal in cardiac muscle elasticity, may be involved in the stiffness that characterizes HFpEF [96]. Additionally, the role of non-coding RNAs and microRNAs in modulating these processes presents a newer area of investigation, with promising therapeutic implications [59, 97].

HFpEF is frequently associated with obesity and metabolic syndrome, where metabolic alterations, such as insulin resistance and dyslipidemia, contribute significantly to cardiac dysfunction [58,98]. Excessive epicardial adipose tissue, known to be metabolically active, secretes numerous inflammatory cytokines that worsen systemic inflammation [99,100]. This interplay between adiposity and cardiac function creates an environment where metabolic disturbances can precipitate or exacerbate HFpEF [101].

Renal dysfunction is another critical comorbidity in HFpEF, further complicating the clinical manifestation of the syndrome. Kidney impairment drives systemic inflammation and fluid retention, amplifying cardiac workload and potentially contributing to the observed diastolic dysfunction [102–104]. Mounting evidence indicates that the kidney actively participates in maintaining a systemic inflammatory state critical to HFpEF pathophysiology [78].

7. Clinical trials testing immunomodulators

Clinical trials conducted in HFpEF patients have been varied in design, objectives, and outcomes, reflecting the complexity and heterogeneity of this condition (Table 6). Despite the initiation of multiple clinical trials, HFpEF trials have faced difficulties. The heterogeneity of the patient population complicates participant recruitment and can potentially dilute treatment effects. This aspect is particularly evident in trials evaluating common treatments, like RAAS inhibitors and beta-blockers, which have often failed to show a clear benefit in mortality or hospitalizations when applied broadly to HFpEF patients [105–107]. Phenotyping, therefore, emerges as a key strategy to better stratify patients in clinical trials based on the underlying pathophysiology.

Table 6.

Main clinical trials testing immunomodulators in HFpEF.

Trial Name/Acronym	Therapeutic Agent or Device	Phase	Targeted Patient Group/Criteria	Main Findings or Purpose
Mitiperstat (AZD4831)	MPO inhibitor	Phase II	HFpEF with elevated MPO-mediated inflammation	Biomarker modulation observed
DHART and D-HART2	Anakinra (IL1β blocker)	Phase II	HFpEF with elevated hsCRP	Significant reduction in CRP
COLpEF	Colchicine	Phase II	HFpEF (inflammationfocused)	Evaluating antiinflammatory effect on symptoms and biomarkers
HERMES	Ziltivekimab (antiIL6 monoclonal antibody)	Phase II – III	HFpEF or HFmrEF with systemic inflammation	Evaluating impact on CV death, HF hospitalizations, urgent visits
JK07	Novel agent in early development	Phase II planned	HFpEF and HFrEF	Dose-dependent biomarker improvements; upcoming randomized trial

The clinical investigation of inflammation and immunology in HFpEF reflects an evolving understanding of the disease as more than a hemodynamic disorder. As mentioned above, increasing evidence implicates systemic and myocardial inflammation, immune cell infiltration, and endothelial dysfunction as central to HFpEF pathophysiology, particularly in patients with multimorbidity – such as obesity, type 2 diabetes, hypertension, and chronic kidney disease – that promote chronic low-grade inflammation and immune activation. Several clinical trials have tested therapies designed to modulate immune and inflammatory signaling. Interleukin-1 (IL-1) has been a major target due to its role in promoting myocardial dysfunction, fibrosis, and systemic inflammation. In the D-HART and D-HART2 trials, anakinra, a recombinant IL-1 receptor antagonist, was evaluated in HFpEF patients with elevated C-reactive protein (CRP) [108,109], demonstrating reductions in CRP and NT-proBNP levels [85]. Similarly, cana-kinumab, an anti-IL-1β monoclonal antibody, showed cardiovascular event reduction in post-MI patients with elevated CRP in the CANTOS trial (NCT01327846), and subgroup analyses have suggested potential relevance to HF populations, though HFpEF-specific data are limited [110,111]. Investigations into the role of colchicine and Coenzyme Q10 supplementation show potential in managing inflammation and improving diastolic function in HFpEF patients [112,113]; their inclusion in ongoing clinical trials reflects the effort to address suboptimal results from earlier studies. Targeting broader inflammatory signaling, the EMPEROR-Preserved trial has evaluated SGLT2 inhibitors, which possess anti-inflammatory and anti-fibrotic properties beyond glycemic control [114], demonstrating reduced HF hospitalizations and improved quality of life, positioning SGLT2 inhibitors as cornerstones of HFpEF therapy [115]; while these agents are not classical immunomodulators, they may attenuate inflammation indirectly by improving metabolic stress, reducing oxidative stress, and altering macrophage polarization [116,117].

Other immunologically relevant targets under investigation include galectin-3, a profibrotic and pro-inflammatory lectin elevated in HFpEF and associated with adverse outcomes. Though no galectin-3–targeting drugs have yet proven efficacy in large HFpEF trials, it remains an attractive biomarker and therapeutic target [118]. Additionally, the JAK-STAT pathway, activated by cytokines and implicated in myocardial hypertrophy and macrophage activation, is being explored in preclinical studies and early-phase trials for its potential to reduce cardiac inflammation and stiffness [119].

Therapies modulating endothelial inflammation and immune cell trafficking have also garnered interest. Soluble guanylate cyclase (sGC) stimulators (e.g. vericiguat) improve NO signaling and might indirectly reduce immune activation, but clinical results were not significant in HFpEF patients [120]. Additionally, novel agents targeting TNF-α, are under conceptual development based on mechanistic models [121], though past studies of TNF-α blockade in HFrEF (e.g. RENEWAL and ATTACH trials [122]) have tempered enthusiasm for direct translation without precision targeting.

These trials highlight an emerging therapeutic paradigm in HFpEF that emphasizes immune modulation and inflammation resolution. However, heterogeneous trial populations, challenges in selecting enriched phenotypes, and the complexity of immune-metabolic interactions in HFpEF continue to limit definitive progress. Future success may hinge on biomarker-driven precision medicine strategies that identify patients most likely to benefit from specific immunologic interventions.

Clinical trials are evolving to address the multifaceted nature of HFpEF, with several studies highlighting the range of therapeutic options, from pharmacologic to device-based interventions. As these trials progress, a clearer understanding of which treatments benefit specific phenotypes of HFpEF patients will emerge, aiding in the quest for more effective management strategies. For instance, device-based therapies like the REDUCE LAP-HF trial are exploring the possibility of shunting to alleviate left atrial pressure and improve clinical outcomes in HFpEF patients. Initial results suggest promise in safely managing symptomatic patients [123,124].

8. Conclusion

The cellular and molecular mechanisms underlying HFpEF are multifaceted, encompassing systemic inflammation, endothelial dysfunction, cardiac fibrosis, and metabolic dysregulation. Understanding the interplay between these factors is critical for developing targeted interventions and improving outcomes for HFpEF patients. HFpEF heterogeneity necessitates phenotypic stratification to guide targeted immunotherapies. Data-driven clustering of clinical and biomarker profiles delineates distinct phenotypes – obesity- and inflammation-dominant, hypertensive-fibrotic, and pulmonary vascular – predominant subgroups – with variable responses to interventions [98,125]. Obesity-associated HFpEF exhibits heightened adipokine-driven inflammation and myocardial metabolic derangements; recent trials with semaglutide provide evidence that weight-reduction strategies improve hemodynamics and attenuate systemic inflammation in this phenotype [98]. Additionally, amyloid (ATTR-CM) – associated HFpEF represents a discrete entity with unique inflammatory signatures necessitating specific therapeutic strategies [126]. Precision medicine approaches integrating clinical, imaging, and multi-omic inflammatory markers promise individualized care in HFpEF [127].

9. Expert opinion

Biomarker-guided risk stratification leveraging composite immune indices enhances HFpEF prognostication and therapeutic monitoring. High-sensitivity C-reactive protein (hs-CRP), MPO, NLR, PLR, lymphocyte-to-monocyte ratio, and systemic immune-inflammation index each correlate with exercise tolerance, hospitalization risk, and mortality in HFpEF [22,74,81]. Proteomic studies reveal dysregulation of acute-phase proteins and extracellular matrix components across the ejection fraction spectrum, providing candidate targets for immunomodulation [31,32,128]. Machine learning models that incorporate inflammatory biomarkers with clinical parameters achieve superior diagnostic accuracy for HFpEF and predict incident events [32,34,129].

Standard HF therapies exhibit ancillary anti-inflammatory effects that may benefit HFpEF patients. SGLT2 inhibitors reduce circulating IL-6 and TNF-α levels, improve endothelial function, and mitigate macrophage activation [130]. Statins exert pleiotro-pic immunomodulatory actions – lowering CRP, stabilizing endothelium, and reducing neutrophil infiltration – but definitive outcome data in HFpEF remain limited [131]. β-blockers demonstrate modest anti-inflammatory effects by attenuating sympathetic-driven cytokine release, though meta-analyses yield mixed efficacy in HFpEF cohorts [131]. Catheter ablation of atrial fibrillation reduces myocardial inflammation and can improve HFpEF outcomes, as investigated in the CABA-HFPEF-DZHK27 trial [132]. A personalized approach to treatment is key, given the diversity of HFpEF phenotypes. Recognition of these distinct phenotypes, driven by specific comorbidities and pathophysiological mechanisms, may guide future therapeutic strategies and clinical trial designs [133,134].

Despite advances, substantial gaps remain in understanding HFpEF immunopathology. The initial triggers of immune activation in early HFpEF are unclear, and the interplay between innate and adaptive immunity over disease progression requires further elucidation. Standardized translational biomarkers and animal models that recapitulate human immune – myocardial interactions are essential for bridging preclinical findings to clinical trials. Furthermore, long-term safety and off-target effects of immunosuppressive therapies necessitate vigilant evaluation. Multidisciplinary efforts across immunology, cardiology, and systems biology are critical to surmount these challenges.

In conclusion, HFpEF is a multisystem inflammatory syndrome in which innate and adaptive immune mechanisms drive endothelial dysfunction, microvascular inflammation, and fibrotic remodeling. Circulating and tissue biomarkers of inflammation offer prognostic and therapeutic guidance, while emerging therapies – including MPO inhibitors, cytokine antagonists, vagal neuromodulation, and precision phenotyping [135]—hold promise for targeted immunomodulation. Continued integration of mechanistic, translational, and clinical research will be pivotal in transforming HFpEF management from symptomatic relief to inflammation-driven, personalized interventions. The management of HFpEF will need to align closely with the unique pathophysiological profile of individual patients, particularly transforming the traditional ‘one size fits all’ approach into more personalized therapeutic strategies. Hence, managing HFpEF necessitates a comprehensive approach that combines pharmacological and non-pharmacological strategies, addressing both symptomatology and associated comorbidities. Ongoing trials and research will undoubtedly help refine these strategies further, guiding clinicians in providing tailored care for this multifaceted syndrome.

Article highlights.

• HFpEF is increasingly recognized as a multisystem inflammatory disorder in which innate and adaptive immune mechanisms drive endothelial dysfunction, microvascular inflammation, and myocardial fibrosis.

• Distinct HFpEF phenotypes – obesity/inflammation-dominant, hypertensive-fibrotic, pulmonary vascular – predominant, and amyloid-associated – display unique immunometabolic profiles, underscoring the need for phenotype-guided, precision immunotherapy.

• Biomarker-based immune profiling (hs-CRP, MPO, NLR, PLR, and systemic immune-inflammation index) enhances prognostication, risk stratification, and therapeutic monitoring in HFpEF.

• Standard HF therapies (SGLT2 inhibitors, statins, β-blockers) exert ancillary anti-inflammatory effects, while novel interventions such as MPO inhibitors, cytokine antagonists, and vagal neuromodulation are emerging as targeted immunomodulatory strategies.

• Future progress hinges on integrating clinical, imaging, and multi-omic inflammatory data, supported by improved translational models, to enable truly personalized, inflammation-driven management of HFpEF.