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

Figures

• 

  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.

• 

  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.

• 

  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…

• 

  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…

• 

  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…