Inflammation, metabolism, and aging in heart failure with preserved ejection fraction: Mechanisms and treatment perspectives

Abstract

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent clinical syndrome with limited effective therapies, representing a major unmet need in cardiovascular medicine. A comorbidity-driven systemic proinflammatory state, together with coronary microvascular endothelial inflammation, has emerged as a central paradigm in HFpEF pathogenesis. Accumulating evidence over the past decade has highlighted the extensive crosstalk between inflammation, metabolic dysregulation, and aging-related processes. In this review, we summarize key advances defining the roles of systemic and microvascular inflammation, metabolic abnormalities, and cellular senescence, and integrate these findings into an interconnected inflammation–metabolism–aging axis in HFpEF. We further discuss the current clinical and emerging preclinical therapeutic strategies targeting these pathways. By linking mechanistic insights with translational perspectives, this review provides a conceptual framework to guide precise therapeutic development for this complex and heterogeneous syndrome.

Introduction

Heart failure (HF) is a clinical syndrome characterized by structural and/or functional cardiac abnormalities, elevated B-type natriuretic peptide levels, and pulmonary or systemic congestion, representing an advanced stage of diverse cardiac diseases. Heart failure with preserved ejection fraction (HFpEF) is defined by a left ventricular ejection fraction of ≥ 50% accompanied by elevated filling pressures.^[1] The prevalence of HF continues to increase, with HFpEF now accounting for approximately half of all cases and occurring more commonly in women.^[2,3] Despite its increasing burden, HFpEF is associated with poor prognosis, with 5-year mortality rates of 50%–75%.^[4] Effective therapies for heart failure with reduced ejection fraction (HFrEF) largely fail in HFpEF, and no treatment has yet demonstrated a significant mortality benefit in this population;^[5] consequently, HFpEF represents a primary unmet clinical need in cardiology.

HFpEF is a clinically heterogeneous syndrome driven by multiple cardiovascular and metabolic risk factors, including obesity, diabetes, hypertension, chronic kidney disease, and aging. It encompasses several overlapping phenotypic subgroups, such as the metabolic‑obese phenotype, older individuals with vascular aging, and relatively younger individuals with low B-type natriuretic peptide levels, among others.^[6,7] Key pathophysiologic processes in HFpEF include left ventricular diastolic dysfunction, left atrial cardiomyopathy, atrial fibrillation, pulmonary hypertension, right ventricular dysfunction, disturbances in autonomic and adrenergic signaling, skeletal muscle dysfunction, and adipose tissue overload.^[8] Notably, rare etiologies such as amyloidosis and hereditary cardiomyopathies are distinct from the more common cardiometabolic forms of HFpEF and are beyond the scope of this review.

Understanding the molecular pathogenesis of HFpEF is essential for the development of effective therapies. Over the past decade, substantial progress has been made in elucidating key mechanisms, particularly systemic low-grade chronic inflammation and its crosstalk with cardiac metabolism and aging, thereby markedly advancing our understanding of HFpEF biology. To integrate these advances, we performed a systematic literature review. A targeted search of PubMed (National Library of Medicine) was conducted using the core term “HFpEF” in combination with “inflammation”, “metabolism”, or “aging”. Retrieved articles were critically appraised, and the principal pathophysiological pathways and emerging therapeutic strategies associated with this axis were identified and synthesized. This primary search was augmented by screening reference lists of seminal reviews and original studies to ensure comprehensive incorporation of both established and recent insights. In this article, we first delineate the roles of systemic and coronary microvascular inflammation, metabolic dysregulation, and aging-related mechanisms in the pathogenesis of HFpEF. We then integrate these components to illustrate their dynamic crosstalk and convergent pathogenic pathways. Finally, we review current and emerging therapeutic strategies that target these interconnected mechanisms. By coupling mechanistic insights with therapeutic developments, this review aims to emphasize the translational potential of HFpEF research.

Paradigm of microvascular inflammation

HFpEF was traditionally regarded as a consequence of hypertensive afterload leading to myocardial hypertrophy and diastolic dysfunction. In 2013, Paulus and Tschöpe proposed a paradigm in which a comorbidity-driven systemic proinflammatory state induces coronary microvascular endothelial inflammation, thereby playing a central role in HFpEF pathogenesis.^[9] This inflammatory process promotes myocardial stiffness and fibrosis and exerts extracardiac effects on the lungs, kidneys, skeletal muscle, adipose tissue, vasculature, and immune system.^{[9, 10, 11]} Unlike the secondary inflammatory response that follows cardiomyocyte loss in HFrEF, systemic inflammation in HFpEF is considered a primary, causal contributor involving multiple interconnected pathophysiologic processes.^[12]

The HFpEF paradigm encompasses several key mechanistic steps and has evolved with accumulating evidence (Figure 1): (1) Comorbidities such as obesity, diabetes, hypertension, chronic kidney disease, and chronic obstructive pulmonary disease trigger chronic systemic inflammation. (2) This systemic proinflammatory state promotes coronary microvascular endothelial inflammation. (3) The inflamed endothelium generates reactive oxygen species (ROS), reduces endothelial nitric oxide synthase activity, and limits nitric oxide (NO) diffusion into cardiomyocytes, thereby attenuating cyclic guanosine monophosphate (cGMP) –protein kinase G (PKG) signaling. (4) Reduced PKG activity promotes cardiomyocyte hypertrophy and increases passive tension through hypophosphorylation of the titin N2B domain. (5) Elevated oxidative and nitrosative stress, driven by proinflammatory cytokines, enhances inducible nitric oxide synthase (iNOS) activity and induces pathologic S-nitrosylation of inositol-requiring enzyme 1α (IRE1α), disrupting the unfolded protein response and impairing protein quality control. (6) In parallel, inflammation induces myocardial interstitial fibrosis and extracellular matrix remodeling via transforming growth factor beta (TGF-β) signaling and immune–fibroblast crosstalk. (7) The combined effects of increased cardiomyocyte stiffness and interstitial fibrosis culminate in diastolic dysfunction and overt HF.

Figure 1.

Paradigm of microvascular inflammation in HFpEF. A comorbidity-driven systemic proinflammatory state induces coronary microvascular endothelial inflammation, which impairs NO–cGMP–PKG signaling, reduces titin N2B phosphorylation, and increases cardiomyocyte stiffness. In parallel, microvascular inflammation recruits macrophages, activates fibroblasts, and promotes ECM remodeling. Oxidative and nitrosative stress further trigger iNOS-mediated S-nitrosylation of IRE1α and aberrant XBP1 signaling, disrupting protein homeostasis and modulating T cell infiltration. Together, these mechanisms contribute to diastolic dysfunction in HFpEF. cGMP: cyclic guanosine monophosphate; ECM: extracellular matrix; eNOS: endothelial nitric oxide synthase; HFpEF: heart failure with preserved ejection fraction; iNOS: inducible nitric oxide synthase; IRE1α: inositol-requiring enzyme 1α; NO: nitric oxide; PKG: protein kinase G; ROS: reactive oxygen species; sGC: soluble guanylate cyclase; XBP1: X-box-binding protein 1; ICAM: intercellular adhesion molecule; VCAM: vascular cell adhesion molecule; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; NF-κB: nuclear factor kappa-B.

Beyond this endothelial-centered framework, cardiomyocyte-intrinsic mechanisms, including mitochondrial dysfunction, metabolic derangement, DNA damage responses, and cellular senescence, among others, also contribute to HFpEF pathogenesis. These mechanisms intersect with inflammation, metabolism, and aging, reflecting the integrated nature of the disease process and the evolving complexity of the HFpEF model. The following sections will examine the evidence supporting each step of this paradigm, as well as the emerging complementary pathways.

Evidence of systemic and myocardial inflammation in HFpEF

HFpEF is characterized by chronic, low-grade systemic inflammation, primarily driven by metabolic comorbidities and aging. This state is evidenced by elevated circulating inflammatory biomarkers and myocardial infiltration by immune cells.^[13] Increased circulating levels of C-reactive protein, interleukins (IL-6, IL-1β, IL-10), tumor necrosis factor (TNF), myeloperoxidase, monocyte chemoattractant protein-1, soluble ST2, growth differentiation factor-15 (GDF-15), and pentraxin-3 have been consistently reported in patients with HFpEF.^{[13, 14, 15]} These biomarkers correlate with disease activity and adverse prognosis.^{[16, 17, 18]} In addition, network analyses of large HF cohorts have identified HFpEF-specific enrichment of inflammatory and extracellular matrix remodeling pathways,^[19] highlighting the central role of inflammation in HFpEF pathophysiology.

Myocardial tissue from patients with HFpEF shows increased infiltration of monocytes, macrophages, neutrophils, and T cells.^[15,20] This immune cell recruitment is driven by endothelial activation and upregulation of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and E-selectin, along with an imbalance in immune cell subsets, characterized by increased T helper 17 (Th17) cells and reduced regulatory T cells.^[21,22] Single-cell RNA sequencing studies in HFpEF mouse models have further demonstrated expansion of proinflammatory macrophage populations that actively drive disease pathogenesis.^[23,24] Cardiac inflammation and oxidative stress are tightly coupled and form a self-perpetuating vicious cycle.^[22,25] Inflammatory mediators such as TNF and TGF-β impair mitochondrial function and promote excessive ROS generation.^[22,25] In turn, ROS induce oxidative DNA damage and activate poly (ADP-ribose) polymerase 1, which triggers the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NLR family pyrin domain-containing 3 (NLRP3) inflammasome pathways, thereby sustaining chronic inflammation and promoting adverse cardiac remodeling.^[25,26]

Coronary microvascular endothelial inflammation in HFpEF

Coronary microvascular dysfunction (CMD) is a prevalent feature of HFpEF and was identified in approximately 75% of patients in the PROMIS-HFpEF study, as reflected by reduced coronary flow reserve and elevated biomarkers of endothelial dysfunction.^[27] CMD is closely linked to common cardiometabolic comorbidities and is associated with subclinical myocardial injury, diastolic dysfunction, and an increased risk of major adverse cardiovascular events, providing a shared pathogenic basis for both HFpEF and microvascular angina.^[28,29] Beyond endothelial-dependent CMD, endothelial-independent impairments in microvascular reactivity show a strong association with mortality in HFpEF,^[30] emphasizing the heterogeneity of CMD in this condition.

Mechanistically, vascular endothelial inflammation represents a major driver of CMD.^[28] Transcriptomic analyses of myocardial tissue from patients with HFpEF demonstrate upregulation of adhesion molecules, including vascular cell adhesion molecule 1, ICAM- 1, and E-selectin, which facilitate leukocyte adhesion, transmigration, and activation.^[21,31] These inflammatory processes promote endothelial dysfunction, impair NO–cGMP–PKG signaling, and disrupt cardiomyocyte relaxation. In mouse models, ICAM-1 deficiency attenuates monocyte and T cell infiltration, reduces cardiac fibrosis, and is associated with lower IL-6 and IL-1β expression, supporting a causal role for endothelial inflammation in CMD and fibrotic remodeling.^[32]

Another important contributor to CMD is coronary microvascular rarefaction, which reflects structural loss of capillaries and impaired angiogenesis.^[28] Transcriptomic profiling of myocardial tissue from patients with HFpEF reveals downregulation of angiogenic pathways.^[33] Diabetes mellitus further exacerbates CMD through systemic microvascular injury, myocardial capillary rarefaction, and impaired angiogenesis, thereby contributing to the development and progression of HFpEF.^[34] Consistent with these findings, single-cell transcriptomic analyses of HFpEF myocardium demonstrate reduced endothelial cell populations characterized by pro-apoptotic and anti-angiogenic gene signatures.^[35] Notably, fibroblasts in HFpEF hearts overexpress angiopoietin-like 4, which inhibits endothelial angiogenesis and promotes collagen deposition, highlighting a pathologic fibroblast–endothelial cell interaction that exacerbates both microvascular rarefaction and fibrosis.^[35]

Role of the NO-cGMP-PKG pathway and titin modifications

The NO–cGMP–PKG signaling pathway plays a central role in the regulation of vascular tone and endothelial function and exerts critical effects on cardiomyocyte physiology.^[13,36] NO, synthesized by endothelial nitric oxide synthase in vascular endothelial cells, diffuses into adjacent vascular smooth muscle cells and cardiomyocytes, where it activates soluble guanylate cyclase (sGC). This activation leads to cGMP production, which, in turn, activates PKG. Under physiologic conditions, this pathway maintains cardiovascular homeostasis by exerting antihypertrophic, antifibrotic, and proangiogenic effects, thereby preventing maladaptive cardiac remodeling.^[36] In pathological states such as inflammation, coronary microvascular endothelial dysfunction is characterized by increased nitrosative and oxidative stress, resulting in reduced expression and activity of endothelial nitric oxide synthase. This leads to diminished NO production and bioavailability, accompanied by increased ROS generation.^[37] Both clinical studies and preclinical HFpEF models consistently demonstrate reduced NO and sGC bioavailability, decreased cGMP levels, and impaired PKG activity.^[21,38] In this setting, reduced PKG activity not only reduces titin phosphorylation, thereby increasing cardiomyocyte stiffness, but also contributes to inflammation, hypertrophy, and fibrosis, all of which drive the progression of HFpEF. ^[10,36]

Titin, a giant sarcomeric protein that is essential for myocardial passive tension, is tightly regulated by the NO–cGMP–PKG pathway and by multiple post-translational modifications that modulate its elastic properties.^[39] In patients with HFpEF, titin shows hypophosphorylation of the N2B domain and hyperphosphorylation of the PEVK domain, both of which increase myocardial passive tension.^[40,41] A shift toward the stiffer N2B isoform relative to the more compliant N2BA isoform has been observed in animal models of HFpEF,^[42] although this change has not been consistently demonstrated in human studies.^[41] Oxidative stress further increases cardiac stiffness in part through redox modifications of titin. In vivo studies show that oxidation of the distal spring elements of titin, via mechanisms such as disulfide cross-linking and unfolded-domain oxidation, alters titin elasticity, promotes domain aggregation, and enhances phosphorylation, collectively contributing to increased passive tension and diastolic dysfunction.^[43]

Nitrosative stress and the unfolded protein response in myocardial dysfunction

Beyond the protective role of NO signaling in endothelial cells, systemic inflammation increases iNOS expression in cardiomyocytes via NF-κB activation. This leads to the production of high concentrations of NO, which directly suppresses sGC activity. In parallel, excess NO rapidly reacts with superoxide anions to form cytotoxic peroxynitrite, inducing nitrosative stress and further exacerbating diastolic dysfunction.^[44] Inhibition or genetic deletion of iNOS prevents obesity-induced CMD in mouse models,^[45] highlighting the critical role of iNOS-mediated nitrosative stress in endothelial-independent CMD and HFpEF.

The unfolded protein response, particularly the IRE1α–X-box-binding protein 1 (XBP1) axis, is downregulated in a double-hit HFpEF mouse model combining a high-fat diet with N^ω-nitro-L-arginine methyl ester treatment, implicating impaired protein quality control in cardiometabolic HFpEF.^[46] Mechanistically, systemic inflammation upregulates cardiomyocyte iNOS expression, promoting pathologic S-nitrosylation of IRE1α and abnormal XBP1 splicing, which leads to protein accumulation and myocardial dysfunction. Consistent with this mechanism, pharmacologic inhibition or genetic ablation of iNOS in mice mitigates mitochondrial dysfunction, oxidative stress, and Akt S-nitrosylation in cardiomyocytes, resulting in improvement of the HFpEF phenotype.^[47] Notably, dysregulation of the IRE1α–XBP1 axis also occurs in T cells in HFpEF mouse models, where it facilitates myocardial T cell infiltration and contributes to cardiac inflammation.^[48]

Mechanisms of inflammation-induced fibroblast activation and myocardial interstitial fibrosis

Systemic inflammation promotes myocardial interstitial fibrosis and extracellular matrix (ECM) remodeling, ultimately contributing to diastolic dysfunction.^[22,28] Increased expression of adhesion molecules on vascular endothelial cells facilitates monocyte recruitment and differentiation into macrophages, which secrete TGF-β and drive fibrotic remodeling.^[21,37,49] TGF-β induces fibroblast-to-myofibroblast differentiation, enhances collagen synthesis, suppresses matrix metalloproteinase activity, and increases tissue inhibitors of metalloproteinases.^[50,51] In parallel, reduced NO bioavailability promotes immune cell adhesion and directly accelerates fibroblast activation.^[28] In addition, NO depletion, oxidative stress, and TGF-β signaling act synergistically to induce endothelial-to-mesenchymal transition, further expanding the fibroblast pool and amplifying myocardial fibrosis.^[28,52]

Immune cell–fibroblast interactions further promote fibroblast activation and myofibroblast differentiation. Cardiac macrophages secrete IL-10, which activates fibroblasts, promotes collagen deposition, and contributes to diastolic dysfunction.^[53] Other immune cells, including dendritic cells, T and B lymphocytes, as well as proinflammatory cytokines such as IL-6, IL-1, and IL-18, also stimulate fibroblast activation.^[22] Activation of NF-κB signaling in fibroblasts promotes monocyte recruitment to the myocardium.^[54] Moreover, fibroblasts can function as antigen-presenting cells by upregulating major histocompatibility complex class II expression in response to interferon-γ, thereby activating CD4⁺ T cells and further exacerbating myocardial inflammation and dysfunction.^[55] These reciprocal interactions underscore the intricate immunofibrotic network that characterizes HFpEF.

Although inflammation is a major driver of fibrosis in HFpEF, emerging transcriptomic data demonstrate profibrotic gene signatures even in the absence of active inflammatory programs, suggesting that ECM remodeling can occur independently of overt inflammation.^[56] Epigenetic mechanisms may also contribute directly. For example, inhibition of histone deacetylases (HDACs) suppresses fibroblast activation by disrupting chromatin recruitment of the profibrotic reader bromodomain-containing protein 4.^[57] Furthermore, overexpression of GATA4 in cardiac fibroblasts reduces fibrosis and improves diastolic function by suppressing fibroblast activation without inducing cardiomyocyte transdifferentiation, highlighting a potential antifibrotic therapeutic strategy.^[58]

Cardiac energy metabolism abnormalities

Metabolic inflexibility

Dysregulated myocardial energy metabolism is a key contributor to the development of HF.^[59,60] Under physiologic conditions, fatty acid β-oxidation supplies approximately 60%–90% of myocardial adenosine triphosphate (ATP), with glucose, ketone bodies, lactate, and other substrates providing complementary contributions.^[60] In HF, the myocardium becomes energetically compromised and loses metabolic flexibility, defined as the capacity to switch adaptively among energy substrates in response to physiologic or pathologic demands.^[11,59,61] Whereas HFrEF is often described as “an engine out of fuel, ” cardiometabolic HFpEF is characterized by fatty acid overload and a forced reliance on fatty acid oxidation, without the compensatory shift toward glucose and ketone utilization typically observed in HFrEF.^[62,63] This distinct metabolic phenotype has led to the emerging concept of “energy resilience” to describe the unique energetic impairments in HFpEF.^[62]

Transcriptomic analyses of human myocardium demonstrate upregulation of mitochondrial ATP synthesis and electron transport pathways in HFpEF compared with control tissue, in contrast to their downregulation in HFrEF.^[33] However, myocardial proteomic studies in patients with severe obesity and HFpEF reveal impaired fatty acid uptake, processing, and oxidation, accompanied by marked lipid droplet accumulation.^[64] Consistent with these findings, metabolomic analyses of HFpEF myocardium show reduced levels of fatty acid metabolism products, tricarboxylic acid cycle intermediates, ketone bodies, and branched-chain amino acid metabolites.^[65] Despite increased expression of glucose transporter type 1, levels of glycolytic and ancillary pathway intermediates, as well as expression of their associated enzymes, are also reduced in HFpEF.^[66] Together, these data indicate that impaired substrate oxidation and utilization underlie metabolic inflexibility and disrupted energy resilience in HFpEF pathogenesis.

Cardiac metabolic remodeling across different comorbidities

Distinct metabolic comorbidities drive specific patterns of cardiac metabolic remodeling. In obesity, elevated circulating free fatty acids lead to excessive myocardial lipid accumulation, including toxic lipids such as diacylglycerols, ceramides, and triglycerides. This lipid overload induces lipotoxicity, mitochondrial dysfunction, and impaired ATP production.^[61,64,67] In pressure overload or ischemic HF, fatty acid oxidation is disrupted, and hypoxia-driven increases in glucose uptake and glycolysis become uncoupled from efficient glucose oxidation, resulting in insufficient energy generation.^[59,60,68] In diabetic cardiomyopathy, both glucose oxidation and glycolysis are reduced, whereas aberrant fatty acid oxidation is increased, promoting glucotoxicity through advanced glycation end-products and O-linked β-N-acetylglucosamine modification, mitochondrial dysfunction, oxidative stress, and activation of cell death pathways.^[59,60,69] Together, these distinct metabolic remodeling processes contribute to the complexity and heterogeneity of metabolic dysregulation observed in HFpEF (Figure 2).^[61,65]

Figure 2.

Metabolic derangements in HFpEF driven by comorbidities. Metabolic comorbidities, including obesity, hypertension, and diabetes, disrupt cardiac substrate utilization and mitochondrial function, leading to metabolic inflexibility in HFpEF. Obesity promotes excess fatty acid accumulation and generation of lipotoxic intermediates that impair mitochondrial ATP production. Hypertensive or ischemic states reduce fatty acid oxidation and uncouple glucose uptake from glucose oxidation, limiting energy generation. In diabetes, suppressed glucose utilization and increased fatty acid oxidation enhance glucotoxicity, oxidative stress, and mitochondrial injury. Impaired mitochondrial quality control through defective mitophagy further contributes to HFpEF pathogenesis. AGE: advanced glycation end product; ATP: adenosine triphosphate; DAG: diacylglycerol; ETC: electron transport chain; FA: fatty acid; FADH2: reduced flavin adenine dinucleotide; HFpEF: heart failure with preserved ejection fraction; LDH: lactate dehydrogenase; NADH: reduced nicotinamide adenine dinucleotide; OAA: oxaloacetate; PDH: pyruvate dehydrogenase; TG: triacylglycerol.

Mitochondrial dysfunction in HFpEF

Mitochondrial dysfunction represents a key abnormality in cardiac metabolism in HFpEF and is characterized by reduced ATP production, increased ROS generation, and structural mitochondrial damage.^[70,71] Ultrastructural analyses of myocardial tissue from patients with HFpEF reveal mitochondrial swelling with cristae separation and dissolution, particularly in individuals with severe obesity.^[64] Importantly, the HFpEF myocardium shows impaired activation of mitophagy, a critical mechanism of mitochondrial quality control.^[72] Accumulation of damaged mitochondria and release of cytosolic mitochondrial DNA (mtDNA) can activate cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) signaling, thereby promoting cardiac inflammation and hypertrophy.^[73] Conversely, stimulation of fatty acid oxidation has been shown to enhance mitophagy, preserve mitochondrial integrity, and confer protection against HFpEF.^[72]

Cardiac aging and cellular senescence

Mechanisms of aging and cellular senescence in HFpEF

Aging is a major risk factor for incident HFpEF, with risk increasing by approximately 90% for every 10-year increase in age.^[74] Although the incidence of both HFpEF and HFrEF rises with advancing age, aging exerts a more pronounced effect on HFpEF.^[74,75] Cellular senescence, defined by irreversible cell cycle arrest associated with aging, is closely linked to cardiovascular diseases, including HF (Figure 3).^[76,77] Senescence can be induced by multiple stimuli, such as ROS, which activate the DNA damage response (DDR) and lead to permanent cell cycle arrest.^[76,78] Senescent cells acquire a senescence-associated secretory phenotype (SASP), characterized by the release of soluble signaling molecules, proteases, and insoluble protein and ECM components. This phenotype promotes a chronic inflammatory state and induces senescence in neighboring cells.^[78]

Figure 3.

Cellular senescence in HFpEF. Cellular senescence in HFpEF arises from DNA damage, mitochondrial dysfunction, chronic inflammation, impaired autophagy and proteostasis, and dysregulated microRNA expression. Oxidative stress-induced DNA damage and telomere attrition activate ATM and ATR signaling and the p53/p21 and p16/Rb pathways, driving irreversible cell cycle arrest. Senescent cells exhibit mitochondrial dysfunction characterized by reduced NAD+ metabolism, impaired respiration, and excess ROS production. Endothelial senescence increases endothelin-1 expression, activating fibroblasts and promoting cardiomyocyte hypertrophy, whereas cardiomyocyte senescence involves STAT1–STING pathway activation. Senescent cardiac cells develop an SASP that propagates senescence through paracrine signaling, collectively promoting endothelial dysfunction, fibrosis, and hypertrophy in HFpEF. ASCC2: activating signal co-integrator 1 complex subunit 2; ATM: ataxia telangiectasia mutated; ATR: ataxia telangiectasia and Rad3-related; DDR: DNA damage response; DSB: double-strand break; HFpEF: heart failure with preserved ejection fraction; NAD+: nicotinamide adenine dinucleotide; NADH: reduced nicotinamide adenine dinucleotide; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; SSB: single-strand break; STAT1: signal transducer and activator of transcription 1; STING: stimulator of interferon genes.

Senescence across multiple cardiac cell types contributes to HFpEF pathogenesis. Endothelial cell senescence plays a central role in microvascular dysfunction. In a mouse model combining accelerated senescence with a high-fat diet, increased levels of acetylated p53, a marker of endothelial senescence, were associated with endothelial inflammation and diastolic dysfunction.^[31] Senescent endothelial cells also upregulate endothelin-1, which promotes fibroblast senescence and collagen production while inducing cardiomyocyte hypertrophy through paracrine signaling.^[28,79] In cardiomyocytes, exposure to interferon gamma induces senescence markers, including p53, p21, and γH2AX, along with activation of the signal transducer and activator of transcription 1 (STAT1) – STING pathway. Notably, these effects can be reversed by the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin.^[80] Although cellular senescence clearly contributes to HFpEF, further studies are needed to delineate the distinct mechanisms by which senescence in specific cell types drives disease progression.

Role of DDR in cellular senescence and HF

Inflammation and oxidative stress are key drivers of aging-related diseases, and DDR plays a critical role in oxidative stress-induced cellular senescence. Excessive ROS generated in the mitochondria and nucleus causes oxidative damage to nuclear DNA, including single-strand breaks (SSBs) and double-strand breaks (DSBs). This damage activates DDR signaling cascades, including ataxia telangiectasia and Rad3-related and ataxia telangiectasia mutated (ATM) kinases, increased γH2AX phosphorylation, and engagement of the p53/p21 and p16/Rb pathways, leading to cell cycle arrest and promotion of cellular senescence or apoptosis.^[76]

Substantial evidence supports a central role for DDR in HF pathogenesis. In pressure overload-induced HF, ROS accumulation and SSBs occur in cardiomyocyte nuclei, a process exacerbated by deletion of the SSB repair protein, X-ray repair cross-complementing protein 1. Persistent unrepaired SSBs sustain DDR activation and upregulate inflammatory cytokine expression through NF-κB signaling, thereby worsening HF.^[81] Markers of DSBs, including γH2AX and phosphorylated ATM, are also elevated in this setting. Inhibition or cardiomyocyte-specific deletion of ATM attenuates cardiac hypertrophy and ventricular remodeling, indicating that excessive DDR activation directly contributes to disease progression.^[82] Consistent with these findings, increased phosphorylated ATM levels have also been observed in HFpEF mouse models.^[83] The DNA repair-associated factor activating signal co-integrator 1 complex subunit 2 (ASCC2) has emerged as a key protective regulator in HFpEF, with loss of its expression inducing HFpEF phenotypes in mice, accompanied by DDR activation and increased expression of proinflammatory cytokines such as IL-6 and TNF.^[83]

Telomere shortening is a fundamental driver of cellular aging.^[84] With each cell division, telomeres progressively erode until reaching a critical length at which the shelterin complex can no longer protect the telomeric loop structure, triggering DDR activation and cell cycle arrest. In human hearts, cardiomyocyte telomere shortening represents a distinct hallmark of HF.^[85] Importantly, telomere dysfunction can also occur independently of telomere shortening. Telomeric DNA damage alone is sufficient to induce cardiomyocyte senescence, activate p21 and p16 signaling pathways, and promote the secretion of noncanonical SASP factors, including GDF-15, TGF-β2, and endothelin-3. These factors collectively contribute to myocardial fibrosis and hypertrophy.^[86]

Crosstalk among inflammation, metabolism, and aging

As discussed above, the preceding sections have summarized the paradigm of systemic and coronary microvascular inflammation, cardiac energy metabolic dysregulation and mitochondrial dysfunction, as well as aging-related cellular senescence and DNA damage in HFpEF. Over the past decade, accumulating evidence has increasingly revealed that these mechanisms engage in extensive bidirectional crosstalk, underscoring the integrative nature of HFpEF pathophysiology. Within this framework, the following sections examine how metabolic comorbidities initiate systemic inflammation, how inflammatory and metabolic perturbations shape cardiac aging, and how diverse metabolites modulate cardiac inflammation and aging in HFpEF. Collectively, these interconnected molecular pathways converge to drive HFpEF pathogenesis (Figure 4).

Figure 4.

Integrated molecular pathways of the inflammation–metabolism–aging axis in HFpEF. EAT releases chemokines that promote immune cell infiltration, macrophage M1 polarization, and myocardial lipotoxicity. Activated macrophages secrete TGF-β, driving fibroblast-to-myofibroblast transdifferentiation, excessive collagen deposition, and myocardial fibrosis. Systemic inflammation induces coronary microvascular endothelial inflammation, leading to impaired NO–cGMP– PKG signaling, reduced titin N2B phosphorylation, and increased cardiomyocyte passive stiffness. In parallel, nitrosative stress disrupts the IRE1α–XBP1 axis, leading to dysfunction of UPR. DAMPs engage PRRs and activate NF-κB signaling, upregulating NLRP3 and pro-IL-1β/IL-18 transcription. Upon stimulation by mitochondrial ROS, the NLRP3 inflammasome assembles and becomes activated, resulting in the maturation and release of IL-1β and IL-18. Mitochondrial dysfunction in HFpEF is characterized by reduced FAO, a metabolic shift toward anaerobic glycolysis, NAD⁺ depletion, and impaired mitophagy. mtDNA released into the cytosol activates the cGAS–STING pathway, enhancing interferon-stimulated gene transcription. Excessive ROS further induce oxidative DNA damage, telomere damage, and DDR activation, thereby promoting cellular senescence and SASP production. Transcriptional programs are further fine-tuned by epigenetic mechanisms, including DNA and histone modifications and miRNA regulation. Collectively, these interconnected pathways converge to drive the development and progression of HFpEF. cGAS: cyclic GMP–AMP synthase; cGMP: cyclic guanosine monophosphate; DAMP: damage-associated molecular pattern; DDR: DNA damage response; EAT: epicardial adipose tissue; ER: endoplasmic reticulum; FAO: fatty acid oxidation; HFpEF: heart failure with preserved ejection fraction; IL-1β: interleukin-1β; IL-18: interleukin-18; IRE1α: inositol-requiring enzyme 1α; miRNA: microRNA; mtDNA: mitochondrial DNA; NAD⁺: nicotinamide adenine dinucleotide; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NLR family pyrin domain-containing 3; NO: nitric oxide; PKG: protein kinase G; PRR: pattern recognition receptor; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; STING: stimulator of interferon genes; TGF-β: transforming growth factor beta; UPR: unfolded protein response; XBP1: X-box-binding protein 1.

Metabolic inflammation in obesity and pressure overload

Metabolic comorbidities are closely associated with systemic inflammation in patients with HFpEF. Elevated IL-6 levels, for example, correlate with greater symptom severity and obesity in this population.^[16] Inflammation-related proteins, including TNF receptor 1, urokinase plasminogen activator receptor, insulin-like growth factor-binding protein 7, and GDF-15 have been identified as key links between metabolic burden and diastolic dysfunction.^[87] The chronic low-grade inflammation associated with obesity, diabetes, and other metabolic disorders—commonly termed metabolic inflammation or meta-inflammation—has emerged as a central concept in HFpEF pathophysiology.^[11] Metabolic diseases sustain systemic inflammation through multiple signaling pathways, whereby metabolic substrates directly modulate gene expression and immune activation. In parallel, inflammation impairs mitochondrial function and disturbs myocardial energy metabolism.^[25,88] This bidirectional reinforcement between inflammation and metabolic dysregulation synergistically accelerates the progression of HFpEF.

Dysregulated lipid metabolism and lipotoxicity play pivotal roles in the activation of immune and inflammatory pathways in obesity. Activation of visceral adipose tissue through hypoxia-inducible factor 1α signaling promotes the accumulation of pro-inflammatory long-chain fatty acids, release of inflammatory mediators, and recruitment of immune cells.^[22,89] Epicardial adipose tissue (EAT) serves as a key site of immune cell aggregation, forming fat-associated lymphoid clusters, where local inflammation and macrophage infiltration are strongly linked to HFpEF development.^[22,90] Expansion of EAT drives adipocytes toward a proinflammatory phenotype, enhancing lipolysis and secretion of cytokines such as leptin, TNF, IL-1β, and IL-6, while reducing adiponectin expression. Adipose-derived chemokines promote macrophage infiltration and polarization toward the proinflammatory M1 phenotype,^[91] further amplifying oxidative stress through IL-1β–dependent mitochondrial ROS production.^[88] Single-cell analyses in hyperlipidemic HFpEF mouse models demonstrate expansion of inflammatory macrophage subsets driven by lipid-induced endoplasmic reticulum stress, which exacerbates cardiomyocyte hypertrophy, fibrosis, and autophagy impairment.^[24] Conversely, overexpression of XBP1 reduces lipid accumulation and myocardial fibrosis by promoting degradation of the transcription factor forkhead box O1, thereby limiting cardiomyocyte lipid deposition.^[92]

Increased hemodynamic load in hypertension promotes ROS generation and proinflammatory cytokine release within the renal and pulmonary vasculature and induces inflammatory cell infiltration into the myocardium.^[13,93] Both hypertension and obesity favor macrophage M1 polarization and myocardial infiltration,^[22,94] while hypertensive hearts also exhibit an imbalance in T cell subsets, characterized by a shift toward proinflammatory Th17 cells relative to regulatory T cells.^[22,95] Damage-associated molecular patterns (DAMPs) released from injured cardiomyocytes in hypertension—including high-mobility group box 1 (HMGB1), heat shock proteins, DNA fragments, oxidized low-density lipoproteins, and mitochondrial contents—activate pattern recognition receptors (PRRs) such as Toll-like receptors, thereby triggering systemic inflammation.^[22,96] The NLRP3 inflammasome is among the most extensively characterized inflammasome sensors in the heart and plays a major role in obesity-related systemic inflammation and insulin resistance.^[97,98] DAMPs and cytokines engage PRRs and cytokine receptors to activate NF-κB signaling, inducing the transcription of NLRP3, pro-IL-1β, and pro-IL-18. Upon activation by stimuli such as mitochondrial ROS and long-chain saturated fatty acids, NLRP3 assembles with apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, leading to caspase-1 activation and subsequent maturation of IL-1β and IL-18.^[98] In addition, increased HMGB1 expression facilitates the formation of neutrophil extracellular traps, which have been shown to mediate diastolic dysfunction in HFpEF mouse models.^[99]

Inflammaging and obesity-induced cardiac aging

Aging is associated with elevated circulating proinflammatory mediators, immune dysfunction, and a chronic inflammatory state, even in the absence of overt immunogenic stimuli.^[100] This age-related, low-grade inflammation—termed inflammaging—substantially increases the risk of HFpEF in older adults.^{[100, 101, 102, 103]} Inflammaging arises from sustained activation of innate immune pathways and involves multiple converging mechanisms, including cellular senescence, mitochondrial dysfunction, impaired autophagy and mitophagy, inflammasome activation, dysregulated ubiquitin–proteasome activity, DDR activation, and altered microRNA expression.^[100,101] The cGAS-STING pathway detects ectopic DNA, including cytosolic mtDNA released from damaged mitochondria, thereby activating type I interferon-mediated innate immune signaling and serving as a key driver of age-associated inflammation.^{[104, 105, 106]} In parallel, age-related alterations in microRNA networks function as epigenetic amplifiers of inflammaging by modulating innate immune signaling, cellular senescence, and metabolic stress responses.^[107,108] Notably, inflammaging and metabolic inflammation are mutually reinforcing processes that share overlapping molecular pathways.^[101,102] This interaction is particularly relevant to HFpEF, given its strong association with aging and cardiometabolic comorbidities.^[11]

Aging is also accompanied by metabolic reprogramming characterized by mitochondrial dysfunction, insulin resistance, a shift from glucose oxidation toward anaerobic glycolysis, and an imbalance between fatty acid uptake and utilization, collectively promoting aging phenotypes and increasing susceptibility to age-related diseases.^[109] Metabolic comorbidities such as obesity can induce premature cardiac aging.^[110] Obesity-related structural and functional cardiac changes—including myocardial hypertrophy, increased stiffness, reduced cardiac reserve, and diastolic dysfunction—closely resemble those observed in aging hearts. Obesity also produces metabolic disturbances that mirror aging-related alterations, and its severity correlates positively with circulating biomarkers of biological aging associated with cardiovascular risk.^[111,112] At the molecular level, obesity and cardiovascular aging share several hallmark features, including mitochondrial dysfunction, impaired proteostasis, genomic instability, cellular senescence, neurohormonal signaling alterations, and chronic inflammation.^[103,110] In particular, visceral adipose tissue contributes to cardiac aging by secreting profibrotic mediators such as osteopontin, which promotes fibroblast senescence, whereas removal of visceral adipose tissue has been shown to attenuate age-related cardiac fibrosis.^[113]

Diverse roles of metabolites in cardiac inflammation and aging

Beyond their role as energy substrates, metabolites function as signaling molecules that regulate inflammation and immune responses.^[11,114,115] The ketone body β-hydroxybutyrate suppresses inflammation in HFpEF models by reversing mitochondrial protein hyperacetylation caused by sirtuin 3 downregulation, thereby inhibiting NLRP3 inflammasome activation and reducing IL-1β and IL-18 production.^[116] Tricarboxylic acid cycle intermediates also modulate inflammatory signaling and epigenetic regulation. α-ketoglutarate exerts anti-inflammatory effects through histone demethylation, whereas low α-ketoglutarate-to-succinate ratio and fumarate accumulation promote proinflammatory gene expression.^[117,118] In classically activated (M1) macrophages, succinate accumulation drives hypoxia-inducible factor 1α activation and IL-1β production.^{[114,115,119]} Although well established, the contribution of these immunometabolic pathways to HFpEF remains incompletely defined.

Nicotinamide adenine dinucleotide (NAD⁺) is a central metabolic cofactor and signaling molecule that serves as a substrate for enzymes involved in DDR, epigenetic regulation, post-translational modifications, and metabolic adaptation to nutritional states.^[120] NAD⁺ and its reduced form, NADH, regulate cellular redox balance, bioenergetics, substrate utilization, and mitochondrial biogenesis and dynamics. Maintenance of NAD⁺ homeostasis is essential for normal cardiac metabolism and function, and reduced NAD⁺ levels have been reported in patients with HFpEF.^[121,122] Aging-associated mitochondrial dysfunction is characterized by declines in NAD⁺ levels and the NAD⁺/NADH ratio, which impair mitochondrial respiration and accelerate cardiac aging. Mitochondrial NAD⁺ depletion disrupts mitophagy and promotes release of mtDNA into the cytosol, thereby amplifying type I interferon responses through activation of the cGAS-STING pathway.^[106] Impaired autophagy, a shared hallmark of aging and HFpEF,^[33,110,123] can be restored by NAD⁺ repletion through suppression of insulin-like growth factor 1 signaling, leading to improvement of HFpEF phenotypes.^[123,124]

During cardiac metabolic remodeling, multiple metabolite-mediated histone and non-histone acylations, including acetylation, lactylation, crotonylation, β-hydroxybutyrylation, succinylation, and O-GlcNAcylation, have been implicated in the regulation of cardiac hypertrophy, aging, and HF.^{[125, 126, 127]} These metabolite-sensitive modifications dynamically respond to nutrient excess, redox imbalance, and hypoxic stress, thereby modulating gene programs associated with cardiac pathology. However, their specific contributions to HFpEF pathogenesis remain incompletely understood. Looking forward, integrative multi-omics approaches, particularly metabolomic profiling, may identify HFpEF-relevant metabolite signatures linked to cardiac aging and disease progression, thus informing mechanism-guided therapeutic development.^[128]

Treatment strategies targeting metabolism, inflammation, and aging

Although HFpEF remains a major clinical challenge, emerging therapeutic strategies increasingly encompass lifestyle interventions, clinically validated pharmacotherapies, and promising preclinical agents (Figure 5). Many of these approaches converge mechanistically on metabolic remodeling, inflammatory regulation, and aging-related pathways (Table 1). Notably, despite improvements in symptoms and reductions in hospitalization achieved with several approved therapies, none has yet demonstrated a consistent reduction in cardiovascular or all-cause mortality in HFpEF. This highlights the biological heterogeneity and therapeutic refractoriness of the syndrome and emphasizes the need for deeper mechanistic insights.

Figure 5.

Lifestyle interventions, pharmacologic therapies, and preclinical targets for HFpEF treatment. Lifestyle modifications—including dietary optimization, exercise training, and management of cardiometabolic comorbidities—are fundamental to improving quality of life and clinical outcomes in HFpEF. Several pharmacologic agents, such as ARNIs, SGLT2 inhibitors, GLP-1 RAs, and nsMRAs, improve symptoms and reduce hospitalizations. Emerging preclinical approaches, including NAD⁺ supplementation, modulation of the NO–cGMP–PKG pathway, HDAC inhibition, and anti-aging strategies, target key mechanisms involving inflammation, metabolism, and aging. ARNI: angiotensin receptor–neprilysin inhibitor; CDC: cardiosphere-derived cell; cGMP: cyclic guanosine monophosphate; DASH: Dietary Approaches to Stop Hypertension; GLP-1 RA: glucagon-like peptide-1 receptor agonist; HDAC: histone deacetylase; HFpEF: heart failure with preserved ejection fraction; HIIT: high-intensity interval training; LIT: low-intensity training; MICT: moderate-intensity continuous training; NAD⁺: nicotinamide adenine dinucleotide; NO: nitric oxide; NP: natriuretic peptide; nsMRA: non-steroidal mineralocorticoid receptor antagonist; PDE: phosphodiesterase; PKG: protein kinase G; sGC: soluble guanylate cyclase; SGLT2i: sodium–glucose cotransporter 2 inhibitor.

Table 1.

Current and emerging pharmacotherapies for HFpEF targeting the inflammation-metabolism-aging axis

Drugs	Primary Targeted Mechanisms	References
Systemic and microvascular inflammation
SGLT2i	Reduce inflammatory and oxidative stress in HFpEF, improve the NO-sGC-cGMP cascade, alleviate myocardial fibrosis.	[142,143]
GLP-1 RAs	Suppress systemic and endothelial inflammation, reduce myocardial fibrosis.	[151,165,166]
nsMRAs	Inhibit excessive activation of mineralocorticoid receptor and RAAS signaling, exert antifibrotic and anti-inflammatory effects.	[153,154]
Metabolism and metabolic-inflammation
SGLT2i	Improve glycemic control, reduce body weight and blood pressure; enhance cardiac energetics, induce ketogenesis and autophagy; reduce epicardial adipose tissue accumulation, inhibit NLRP3 inflammasome activation.	[140,141,167,168,169,170]
GLP-1 RAs	Improve glucose homeostasis, blood pressure, reduce appetite, adiposity and inflammation.	[170,171]
NAD+ Precursors	Enhance myocardial bioenergetics and metabolic flux, improve mitochondrial function and redox balance, restore autophagy and mitophagy.
Aging and inflammaging
SGLT2i	Enhance clearance of senescent cells via immunosurveillance.	[144]
NAD+ Precursors	Enhance myocardial bioenergetics and mitochondrial function during aging, activate sirtuins to counteract senescence.	[122,172]
Senolytics	Clearance of senescent cells, attenuate inflammation, cardiac fibrosis and endothelial rarefaction.	[86,161]

Lifestyle interventions

Lifestyle interventions, including optimization of dietary patterns, increased physical activity, weight loss, and improved control of cardiovascular risk factors, are fundamental to HFpEF management.^{[129, 130, 131]} Dietary modification plays a key role; adherence to plant-based dietary patterns is inversely associated with incident HF, whereas Southern dietary patterns show a positive association with HF risk.^[130,132] Sodium restriction alleviates congestion and edema and improves quality of life and clinical outcomes. In patients with hypertensive HFpEF, the sodium-restricted Dietary Approaches to Stop Hypertension (DASH) diet is associated with improvements in diastolic function, arterial elasticity, and ventricular–arterial coupling.^[133] Calorie restriction exerts favorable effects on cardiorespiratory fitness, insulin sensitivity, glucose metabolism, and lipid profiles, as well as reductions in body weight, inflammatory burden, and oxidative stress.^[129] Intermittent fasting has emerged as a promising strategy to improve cardiometabolic risk factors and cardiovascular outcomes, potentially through circadian alignment and modulation of insulin sensitivity, inflammation, and lipid metabolism.^[134] Exercise interventions, including high-intensity interval training, moderate-intensity continuous training, and low-intensity training, consistently improve peak oxygen consumption in patients with HFpEF.^[131] Mechanistically, exercise restores skeletal-muscle fatty-acid and branched-chain amino-acid oxidation, thereby improving exercise capacity in a mouse model of cardiometabolic HFpEF.^[135] In addition, exercise training protects against cardiac aging and attenuates aging-related pathways in aged mouse models of HFpEF.^[136,137] Overall, lifestyle interventions enhance quality of life, exercise capacity, and prognosis, although long-term adherence and the precise mechanisms underlying their benefits require further investigation.

Clinically proven effective medications for HFpEF

SGLT2 inhibitors

SGLT2 inhibitors have emerged as first-line therapy for HFpEF.^[4] These agents improve glycemic control, reduce body weight and blood pressure, and confer cardiovascular benefits.^[138] Mechanistically, SGLT2 inhibitors modulate metabolic state, enhance autophagic flux, promote ketogenesis and erythropoiesis, and counteract insulin resistance.^{[139, 140, 141]} In addition, SGLT2 inhibitors reduce EAT accumulation, inhibit NLRP3 inflammasome activation, improve systemic metabolic and inflammatory profiles, and reduce myocardial fibrosis.^[24,139,142] Consistent with the microvascular inflammation paradigm, empagliflozin reduces myocardial ICAM-1, vascular cell adhesion molecule 1, TNF, and IL-6 expression, attenuates cardiomyocyte oxidative stress, and improves myocardial compliance by enhancing the NO–sGC–cGMP cascade and PKG1α activity.^[143] Besides, SGLT2 inhibitors also promote clearance of senescent cells through enhanced immunosurveillance.^[144] Beyond cardiac effects, SGLT2 inhibitors slow renal function decline by reducing transglomerular pressure, modulating tubuloglomerular feedback, and constricting afferent arterioles, with synergistic benefits alongside renin–angiotensin–aldosterone system (RAAS) inhibition. These combined cardiovascular and renal effects underpin their clinical efficacy in HFpEF.^[145]

Glucagon-Like peptide-1 receptor agonists (GLP-1 RAs)

GLP-1 RAs improve glucose homeostasis through actions on pancreatic islet cells, regulation of gastric emptying, and central nervous system pathways, leading to reduced appetite, body weight, blood pressure, adiposity, and systemic inflammation.^[146] The STEP-HFpEF trial demonstrated significant clinical benefits of semaglutide in patients with obesity-related HFpEF, including symptom improvement, enhanced exercise tolerance, and reduced inflammatory burden.^[147] Treatment with tirzepatide, a long-acting dual agonist of glucose-dependent insulinotropic polypeptide and GLP-1 receptors, was also associated with lower cardiovascular risk in obesity-related HFpEF; however, these benefits were driven primarily by reductions in worsening HF events rather than cardiovascular mortality.^[148] In preclinical studies, liraglutide improved cardiac metabolism, attenuated ventricular hypertrophy and fibrosis, preserved cardiac structure and function, and reduced circulating natriuretic peptide levels in a multi-hit mouse model of HFpEF.^[149] Liraglutide also increased endothelial eNOS expression, reduced ICAM-1 levels, and enhanced PKG signaling in cardiomyocytes.^[150,151] As interest in GLP-1 RAs continues to grow, further studies are needed to confirm their efficacy across distinct HFpEF subgroups, clarify effects on hard clinical endpoints, and elucidate underlying molecular mechanisms.

Nonsteroidal mineralocorticoid receptor antagonists

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist with greater receptor-binding affinity and selectivity, a shorter plasma half-life, and a lower risk of hyperkalemia than spironolactone and eplerenone.^[152] By inhibiting excessive activation of mineralocorticoid receptor and RAAS signaling, finerenone exerts antihypertrophic, antifibrotic, and anti-inflammatory effects, conferring clinically meaningful cardiorenal benefits.^{[153, 154, 155]} In the FINEARTS-HF trial,^[156] finerenone reduced the primary composite outcome of total worsening HF events and cardiovascular death by 16% in patients with HFpEF and mildly reduced ejection fraction, while also improving quality of life. The reduction was largely driven by an 18% decrease in worsening HF events, with no significant effect on cardiovascular mortality. Subgroup analyses showed similar treatment effects regardless of concomitant SGLT2 inhibitor use. The ongoing CONFIRMATION-HF trial (NCT06024746) is evaluating the efficacy and safety of combined finerenone and SGLT2 inhibitor therapy compared with standard care in hospitalized patients across the full spectrum of ejection fraction.

Potential preclinical therapeutic targets NAD⁺

Preclinical studies demonstrate that supplementation with NAD⁺ precursors, such as nicotinamide and nicotinamide riboside, improves diastolic dysfunction in aging and cardiometabolic HFpEF models.^[121,122] Activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage pathway, confers similar benefits. Mechanistically, nicotinamide enhances myocardial bioenergetics by promoting weight loss, shifting substrate metabolism utilization toward fatty acid β-oxidation, and deacetylating key regulators of diastolic function, thereby improving cardiomyocyte passive tension and calcium handling.^[122] Additionally, nicotinamide restores autophagy and mitophagy in obesity-related HFpEF models.^[123,124] Collectively, these findings identify NAD⁺ augmentation as a promising therapeutic strategy, warranting further clinical investigation.

Targeting the NO–cGMP–PKG pathway

Although the NO–cGMP–PKG pathway is central to HFpEF, most clinical trials targeting this axis—including NO donors, natriuretic peptides, sGC stimulators, and phosphodiesterase (PDE) inhibitors—have shown neutral or inconsistent results.^[36] Proposed explanations include nitrosative stress,^[36,46] and compartmentalization of cGMP signaling within cardiomyocytes.^[13] cGMP generated via the NO–sGC–PDE5 pathway is restricted to the Z-disc and subject to feedback inhibition, limiting phosphorylation of myofilament proteins such as titin.^[13] In contrast, natriuretic peptide–particulate guanylyl cyclase–PDE9 signaling localizes closer to titin, contributing to benefits observed with angiotensin receptor–neprilysin inhibitors.^[157] Vasodilator-induced hypotension further limits NO-based therapies. Ongoing trials evaluating more targeted modulation of this pathway may clarify therapeutic potential.

HDAC inhibitors

HDAC inhibitors, currently approved for several malignancies, demonstrate cardioprotective effects in HFpEF models by reducing fibrosis, inhibiting collagen synthesis, and reversing ventricular hypertrophy.^[158] These agents improve diastolic function by enhancing myofibrillar relaxation ^[159] and attenuating pathological ECM remodeling.^[57] However, adverse effects, including arrhythmias, atherosclerosis, and vascular calcification,^[160] limit clinical applicability. More selective approaches to HDAC modulation are therefore required.

Anti-Aging and cardiac regeneration strategies

Anti-aging strategies include senolytics, senostatics, and SASP inhibitors.^[78] In preclinical models, senolytics reduce cardiomyocyte hypertrophy and fibrosis, along with attenuating systemic inflammation and endothelial rarefaction.^[86,161] Furthermore, improved diastolic relaxation was demonstrated in a human heart-on-a-chip model with dasatinib and quercetin.^[162] Nevertheless, their long-term safety and efficacy remain uncertain. Cardiac regeneration approaches, such as cardiosphere-derived cell therapy, improve diastolic function in experimental models via antifibrotic and anti-inflammatory mechanisms,^[163] partly mediated by inhibition of protein kinase C β.^[164] While promising, these strategies remain experimental and require further validation.

Summary and future perspectives

Over the past decade, comorbidity-driven systemic inflammation has emerged as a central framework for understanding HFpEF pathogenesis. This concept has expanded beyond a purely microvascular model. Growing evidence indicates that cardiomyocytes exhibit intrinsic dysfunction, including altered titin phosphorylation, mitochondrial impairment, oxidative and nitrosative stress, and maladaptive metabolic reprogramming. Importantly, these changes may occur independently of endothelial injury, suggesting that cardiomyocyte stress can function as an initiating or parallel driver of disease rather than solely a downstream consequence. Although inflammation remains a core feature, its predominant sources, whether endothelial cells, cardiomyocytes, immune cells, or adipose tissue, may vary across HFpEF subtypes, representing a critical area for future investigation.

Recent studies highlight the interplay among immune activation, metabolic dysregulation, and aging, now conceptualized within the emerging inflammation–metabolism–aging framework that underpins HFpEF pathophysiology. As understanding of these interconnected mechanisms expands, novel therapeutic targets are being identified, creating new opportunities for treatment development. The field is increasingly moving away from a one-pathway-fits-all approach toward a precision medicine paradigm that acknowledges the marked heterogeneity of HFpEF phenotypes. In this context, biomarker-guided patient stratification constitutes a pivotal step toward precision medicine in HFpEF. Given that inflammation, metabolic dysregulation, and aging-related pathways differentially dominate disease progression among patients, contributing to the intrinsic heterogeneity of HFpEF, specific biomarkers could be employed to identify the predominant pathophysiological phenotype in each patient. This stratification would permit rational allocation of targeted therapies, such as anti-inflammatory, metabolic, or senescence-modulating agents, to individuals most likely to benefit, thereby shifting from phenotype-based classification to mechanism-based treatment.

Several key questions remain to be addressed to advance mechanistic insight and therapeutic development in HFpEF: (1) Molecular targets: Determining actionable molecular pathways and targets that regulate inflammation, energy metabolism, aging, and their mechanistic convergence in HFpEF; (2) Cellular interactions: Elucidating the roles and interrelationships of cardiomyocytes, endothelial cells, fibroblasts, macrophages, and other cell types at single-cell resolution; (3) Inter-organ crosstalk: Defining systemic interactions among the heart, kidney, liver, brain, and skeletal muscle to more accurately characterize HFpEF as a multisystem disorder; (4) Clinical heterogeneity: Identifying molecular determinants underlying phenotypic variability, including sex-related differences and distinct HFpEF subgroups; (5) Divergence from HFrEF: Clarifying the mechanisms that differentiate HFpEF from HFrEF across the heart-failure continuum; (6) Translational advances: Accelerating the translation of mechanistic discoveries into precision biomarkers and effective therapies for HFpEF.

Given its complexity, multisystem involvement, and substantial clinical heterogeneity, HFpEF necessitates a multidisciplinary research approach. Integration of basic, translational, and clinical investigations will be essential to advance understanding and to develop effective, personalized therapeutic strategies for this challenging condition.

Funding Statement

This work is supported by National Natural Science Foundation of China (No. 82200430, No. 32230019), CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2025-I2M-XHCL-007, No. 2025-I2M-XHZY-004), and Peking Union Medical College Hospital Talent Cultivation Program (Category D) No. UHB12605.