The Mechanisms Associated with Inflammation and Coronary Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction

Authors: Xiaoli Yan, Ruxia Wang, Hui Xu, Zhongbin Tao, Jizu Ling

Abstract

Heart failure is a complex clinical syndrome, with more than half of the cases classified as heart failure with preserved ejection fraction (HFpEF). HFpEF is strongly associated with comorbidities such as hypertension, obesity, diabetes, anemia, chronic kidney disease, chronic obstructive pulmonary disease, advanced age, and female gender. Despite its high prevalence, the exact pathogenesis of HFpEF remains poorly understood, leading to limited therapeutic options and poor prognosis. Recently, a novel paradigm has emerged, suggesting that comorbidities drive myocardial dysfunction and remodeling in HFpEF through coronary microvascular inflammation. This review summarizes the molecular mechanisms linking inflammation to coronary microvascular dysfunction in HFpEF and discusses current therapeutic strategies targeting these pathways.

Highlights of the Study Heart failure with preserved ejection fraction accounts for a significant proportion of heart failure and is associated with significant morbidity and mortality.Chronic comorbidities contribute to a systemic low-grade proinflammatory state, which triggers myocardial dysfunction and structural alterations leading to heart failure with preserved ejection fraction.Therapeutic strategies targeting inflammation and coronary microvascular dysfunction may offer promising therapeutic strategies for heart failure with preserved ejection fraction patients.

Introduction

Heart failure (HF) is a clinical syndrome characterized by symptoms and/or signs of structural and/or functional cardiac abnormalities, confirmed by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion [1]. Heart failure with preserved ejection fraction (HFpEF), or diastolic HF, is defined by typical HF symptoms and a normal left ventricular (LV) ejection fraction (≥50%), often with elevated natriuretic peptides and evidence of diastolic dysfunction or structural heart disease [2]. HFpEF accounts for nearly 50% of all HF cases and is associated with substantial morbidity and mortality [3].

Unlike heart failure with reduced ejection fraction (HFrEF), for which effective therapies exist, treatments for HFpEF remain inadequate [4]. Chronic comorbidities such as hypertension, type 2 diabetes mellitus, obesity, and renal insufficiency frequently precede the onset of HFpEF [5, 6]. A new conceptual model proposes that systemic low-grade inflammation induced by comorbidities leads to coronary microvascular dysfunction (CMD), triggering myocardial structural and functional changes [7]. CMD promotes endothelial oxidative stress, reduces nitric oxide (NO) bioavailability, and leads to cardiomyocyte hypertrophy, stiffness, and fibrosis hallmarks of diastolic dysfunction and HFpEF [7, 8]. In this review, we explore the intricate interplay between inflammation, CMD, and HFpEF pathophysiology and discuss emerging therapeutic strategies targeting these mechanisms.

Chronic Low-Grade Inflammation in HFpEF

Inflammation is now recognized as a key driver of heart damage in both HFrEF and HFpEF. Based on underlying trigger, the inflammation associated with HF can be classified into three sterile, metabolic, and non-sterile-induced inflammation [4]. HFrEF is primarily driven by sterile inflammation, which occurs due to coronary artery disease, tissue necrosis following post-ischemic damage, toxic exposure, acute physical trauma, hemorrhage, or resuscitation. Non-sterile inflammation, often triggered by viral infection, also plays a role in the progression of HFrEF. Both forms are associated with cardiomyocyte damage or necrosis [4, 9].

In contrast, HFpEF is largely driven by extracardiac comorbidities – including obesity, diabetes, anemia, hypertension, chronic obstructive pulmonary disease, autoimmune disease, and chronic kidney disease, all of which contribute to a state of chronic low-grade inflammation, often referred to as metabolic risk inflammation [10]. Recent studies have shown that biomarker profiles associated with HFrEF are linked to cellular proliferation and metabolic processes, which in turn promote systemic inflammation in HFpEF [7, 10].

As symptoms and signs of HFpEF are nonspecific, many studies over the years have focused on identifying inflammatory biomarkers. The BIOSTAT-CHF study found distinct biomarker networks in HFpEF, emphasizing inflammation and matrix remodeling [11]. Growth differentiation factor 15 (GDF15), highly expressed in states of inflammatory stress, correlates with the presence and severity of HFpEF [12]. Other inflammatory markers, including soluble suppression of tumorigenicity2 (sST2), C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor-alpha (TNF-α), TNF receptor 1 (TNFR1), IL1R1, have also been associated with HFpEF [13–19]. The currently identified biomarkers of HFpEF were summarized in Table 1.

Inflammation and CMD

Coronary Microvascular Dysfunction

In a prospective observational study, Dryer et al. [20] first reported coronary CMD in patients with HFpEF. The coronary microcirculation comprises arterioles, venules, and capillaries responsible for nutrient exchange between the vasculature and myocardium [21]. CMD can arise from either endothelial dysfunction or vascular smooth muscle dysfunction (endothelium-independent) [22]. Based on physiologic assessment in the catheterization laboratory, CMD can be classified into structural CMD and functional CMD [23]. The primary mechanisms of CMD includes three aspects as increased coronary systolic responsiveness at both the epicardial and microvascular levels, impaired endothelium-dependent and endothelium-independent coronary vasodilator capacities, and elevated coronary microvascular resistance due to structural factors, with inflammatory mediators playing a key role in these processes [24, 25].

Microvascular spasm involves Rho-kinase-mediated phosphorylation of myosin light chain in smooth muscle cells [26], increased production of vasoconstrictors (e.g., serotonin) [27], and inflammatory activation of the coronary microvasculature [25]. Considerable evidence suggests that coronary endothelial dysfunction is central to impaired coronary microvascular vasodilation. The imbalance between endothelial-derived relaxing factors (NO, prostacyclin [PGI2], EDH factors), and contractile factors (ET-1, superoxide, hydrogen peroxide, and thromboxanes) contributes to endothelial-dependent dysfunction [8, 28–31]. On the other hand, endothelial-independent dysfunction occurs due to changes in vascular tone resulting from an imbalance between vasoconstrictors (e.g., angiotensin II) and vasodilators (e.g., adenosine) acting on vascular SMCs. Endothelial-independent dysfunction is present in approximately 33% of patients with HFpEF, and it correlates with worse diastolic dysfunction and outcomes compared to endothelial-dependent dysfunction [32].

Current invasive tests used to diagnose CMD assess the ability of microvessels to increase blood flow in response to vasodilator stimulation, a measure known as coronary flow reserve (CFR) [23, 33, 34]. Endothelium-independent CMD is defined as a CFR of <2.5 in response to adenosine, while endothelium-dependent CMD is typically diagnosed during acetylcholine testing by the presence of anginal symptoms and/or ischemic ECG changes with no obstructive coronary artery disease, rather than by changes in CFR <1.5 alone [33–35]. Numerous structural changes or microvascular remodeling are associated with CMD, leading to structural CMD, including luminal narrowing, vascular remodeling, vascular rarefaction, and extramural compression [36]. Microvascular rarefaction, which refers to a reduction in myocardial microvascular density, was observed in the myocardium of HFpEF patients in biopsy samples [37]. In these patients, microvascular rarefaction contributes to cardiac hypoperfusion by impairing myocardial oxygen delivery [38]. Furthermore, myocardial fibrosis increases as inflammatory conditions in the coronary microvasculature decrease, resulting in enhanced coronary vasoconstrictive reactivity [37].

Mechanics of Endothelial Cells in Regulating Vascular Tone

Growing evidence highlights the critical role of chronic low-grade vascular inflammation in the underlying mechanisms of CMD [37]. Tona et al. [39] demonstrated that IL-6 and TNF-α were the sole determinants of CFR <2.5, suggesting that coronary microvascular impairment is closely linked to inflammation. Endothelial dysfunction, both structural and functional, is central to CMD development. Systemic inflammation activates coronary microvascular endothelial cells (CMECs), inducing the expression of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin. These promote leukocyte adhesion and transendothelial migration, amplifying local inflammation [40, 41]. Proinflammatory cytokines can also induce reactive oxygen species (ROS) production in ECs via NADPH oxidase activation [42], increasing oxidative stress. NO, a soluble gas continuously synthesized from l-arginine in ECs by the calmodulin-dependent enzyme nitric oxide synthase (NOS) [43], serves as a crucial homeostatic regulator that modulates vascular SMCs, cardiomyocytes, and fibroblasts, thereby playing a pivotal role in the pathophysiology of HFpEF [10]. Endothelial NOS (eNOS) dysfunction and increased inducible NOS activity are key contributors to CMD in the pathogenesis of HFpEF [10, 44]. A systemic inflammatory state elevates endothelial ROS production [45], which reacts with NO to form peroxynitrite, leading to eNOS uncoupling and decreased NO production and bioavailability. Reduced NO availability leads to diminished cyclic guanosine monophosphate (cGMP) levels and protein kinase G (PKG) activity [22]. Compared to patients with HFrEF, myocardial biopsies from HFpEF patients revealed decreased NO bioavailability, increased eNOS uncoupling, and significantly reduced cGMP concentrations and PKG activity [41, 46]. PKG can also be directly modified by oxidative stress. Additionally, oxidative stress directly impairs PKG signaling via post-translational modifications such as oxidation of the PKGIα isoform [47]. EDH factors, such as hydrogen peroxide (H2O2), also contribute to microvascular dilation, particularly in small resistance vessels like coronary arterioles [48]. In HFpEF, oxidative stress and eNOS uncoupling impair the production of both NO and EDH factors, further compromising myocardial perfusion and diastolic function [49, 50]. The simplified mechanisms by which endothelial cells contribute to the development of CMD are illustrated in Figure 1.

Inflammation and CMD in HFpEF

Cardiac remodeling is a key pathological feature of HFpEF, characterized by alterations in cardiac morphology, structure, and function [51]. Mounting evidence supports the central roles of inflammation, oxidative stress, and CMD in driving this remodeling process [8]. A key mechanism in the development of CMD is the structural or functional damage of CMECs [52]. Endothelial dysfunction is not only one of the earliest events in HFpEF but also one of the most severe [4]. There are complex interactions between ECs, cardiomyocytes, fibroblasts, and the extracellular matrix (ECM). Dysfunction in ECs is, therefore, a critical mechanism contributing to CMD [8].

Titin and Myocardial Stiffness

Titin is a giant cytoskeletal protein that spans from the Z disc to the M band of the sarcomere, acting as a molecular spring that maintains passive tension, elastic recoil, and contributes to diastolic and systolic coupling in cardiomyocytes [53, 54]. The I-band region of titin includes two extensible tandem immunoglobulin (Ig) domains and unstructured regions, such as the N2B unique sequence (N2Bus) and the PEVK region, which are rich in proline, glutamate, valine, and lysine residues [54, 55]. Titin stiffness is modulated by isoform expression, phosphorylation, and oxidative modifications [56–58]. Alternative splicing of titin mRNA generates two the shorter but stiffer N2B and the longer, more flexible N2BA [4]. In HFpEF models, a shift toward N2B contributes to increased myocardial stiffness [56]. Inhibition of the splicing factor RNA-binding motif 20 (RBM20) increased N2BA and improved cardiac diastolic function [59].

In addition to isoform switching, site-specific phosphorylation of titin allows rapid modulation of its mechanical properties [4]. Phosphorylation of N2Bus by protein kinase A (PKA), protein kinase G (PKG), or CaMKIIδ reduces passive stiffness, whereas phosphorylation of the PEVK region by PKCα or CaMKIIδ increases stiffness [54]. In HFpEF, systemic inflammation and CMD reduce endothelial NO production, impairing NO-cGMP-PKG signaling in adjacent cardiomyocytes [10, 22]. This leads to hypophosphorylation of titin, particularly of the N2B segment, resulting in elevated passive tension and reduced myocardial compliance [56, 57, 60]. Additionally, oxidative stress promotes disulfide bond formation within the N2Bus region, leading to internal cross-linking and a loss of extensibility, which ultimately increases passive tension in cardiomyocytes [61].

Effects of Inflammation and CMD on Cardiac Fibrosis

Cardiac fibrosis is a central pathological feature of HFpEF, contributing to myocardial stiffness and diastolic dysfunction [62]. Histopathological analysis categorizes cardiac fibrosis into 3 repairing fibrosis, interstitial fibrosis, and perivascular fibrosis [63]. In HFpEF, interstitial fibrosis and perivascular fibrosis are the predominant forms [4]. The transformation of fibroblasts into myofibroblasts is a crucial cellular event in many fibrotic conditions [63].

Although the activation of fibroblasts is a key process in cardiac fibrosis, ECs also play an essential role in this pathological process [62]. In response to inflammation and oxidative stress, damaged CMECs undergo endothelial-to-mesenchymal transition (EndMT), losing their endothelial characteristics and gaining fibroblast-like properties. These changes contribute to ECM expansion, increased myocardial tissue stiffness, and reduced cardiac compliance [62, 64]. Multiple signaling pathways, including TGF-β, Notch, Wnt, oxidative stress, hypoxia, and microRNA, are involved in the process of EndMT in cardiac fibrosis [64]. Among these, TGF-β is the most significant signaling pathway [65]. These pathways promote the progression of cardiac fibrosis by regulating various transcription factors, such as the Snail family of zinc finger transcription factors (Snail, Slug, Twist) and Zeb transcription factors (Zeb1 and Zeb2) [8, 66].

In addition to EndMT, activated ECs can exert profibrotic effects by secreting paracrine factors such as connective tissue growth factor (CTGF), TGF-β1, and ET-1, which stimulate fibroblast proliferation, differentiation, and ECM accumulation [8]. Moreover, in the systemic inflammatory state induced by comorbidities, circulating immune cells and cytokine levels are elevated, and the levels of coronary endothelial cell adhesion molecules are upregulated. This promotes the recruitment of circulating inflammatory cells, especially monocytes and Th1 cells [67, 68]. Monocytes differentiate into macrophages after penetrating the endothelium, expressing profibrotic mediators such as TGF-β and interferon-γ (IFN-γ), and facilitating the transformation of fibroblasts into myofibroblasts [29, 69, 70].

CMD and Myocardial Hypertrophy in HFpEF

Myocardial hypertrophy is another key structural feature of HFpEF, primarily characterized by concentric LV hypertrophy driven by increased wall stress and altered myocardial signaling [71]. Unlike hyperplasia, cardiomyocyte hypertrophy involves an increase in cell size via the expansion of myonuclear units [72]. In the update paradigm, chronic inflammation induces structural and functional disturbances in the coronary microvasculature, leading to an imbalance in the exchange of blood flow between the microvasculature and the myocardium. CMECs communicate with adjacent cardiomyocytes by releasing of growth factors such as NO, ET-1, and neuregulin-1 (NRG-1) [8]. NO, through the NO-cGMP-PKG pathway, acts as a negative regulator of myocardial hypertrophy by inhibiting calcium-dependent pro-hypertrophic signals, such as the calcineurin-NFAT and TRPC channel pathways [73, 74]. The S1P/S1PR1 signaling pathway increases NO production in ECs by activating the AKT/eNOS pathway [75]. In contrast to NO, ET-1 promotes myocardial hypertrophy. ET-1 stimulation induces cardiomyocyte hypertrophy, accompanied by a decreased expression of the cytoprotective heat shock protein heme oxygenase-1 (HO-1) both in vivo and in vitro [76]. Angiotensin II (Ang II) stimulates the transcription of ET-1, contributing to myocardial hypertrophy and fibrosis. The myocardin-related transcription factor A (MRTF-A) mediates Ang II-induced transcription of ET-1, and MRTF-A deficiency alleviates Ang II-induced myocardial hypertrophy and fibrosis in mice, while reducing ET-1 synthesis and release [77].

The NRG-1/ErbB system is an endothelial-controlled paracrine signaling pathway in which vascular endothelial growth factor (VEGF) induces NRG-1 secretion from ECs. Incubating cardiomyocytes with conditioned medium from VEGF-treated ECs leads to increased phosphorylation of AKT, promoting myocardial hypertrophy [78]. During the development of cardiac hypertrophy, corresponding growth of coronary vessels is necessary to supply adequate oxygen and nutrients to the hypertrophic myocardium. Cardiomyocytes, in turn, influence ECs through various paracrine signals, including ET-1, fibroblast growth factor 2, and VEGF-A. These signals affect vascular tone, growth, and development of coronary vessels, contributing to an imbalance in the vascular/myocardial ratio [72, 79], which ultimately drives cardiac hypertrophy and HF.

Impaired UPR in HFpEF

The endoplasmic reticulum (ER) is essential for protein synthesis, folding, calcium homeostasis, and lipid metabolism. Under ER stress conditions, accumulation of misfolded proteins activates the unfolded protein response (UPR), a protective mechanism that halts protein translation, enhances chaperone expression, and promotes degradation of unfolded proteins to restore ER function. In HFpEF, a defective UPR has been implicated in increased LV stiffness, independent of fibrosis and titin alterations [7]. Chronic inflammation elevates inducible NOS expression in cardiomyocytes, leading to S-nitrosylation of key UPR regulators, particularly IRE1α [80]. Studies have demonstrated that downregulation of XBP1 is closely associated with the development of HFpEF. The spliced form of XBP1s is reduced in the myocardium of both experimental and human HFpEF cases, and overexpression of XBP1s in cardiomyocytes has been shown to partially improve diastolic function in HFpEF mice [81]. The cardioprotective effect of XBP1s-mediated UPR is modulated through the transcription of STUB1, an E3 ubiquitin ligase that triggers the ubiquitination and degradation of Forkhead box protein O1 (FoxO1). FoxO1 has been shown to promote lipid accumulation in cardiomyocytes and contribute to the pathogenesis of HFpEF [82]. Recent research has also identified the accumulation of misfolded proteins in clinical HFpEF, particularly in elderly patients, by detecting wild-type transthyretin amyloidosis [83]. This suggests that protein quality control mechanisms are emerging as an important area of focus in HFpEF pathophysiology.

Infiltrative Cardiomyopathies

In addition, infiltrative cardiomyopathies, such as amyloidosis, sarcoidosis, as well as storage disorders including Fabry disease, hemochromatosis, and glycogen storage diseases, can also present with a cardiac phenotype dominated by diastolic dysfunction. These conditions contribute to impaired diastolic function through deposition of abnormal proteins or granulomatous inflammation within the myocardium, leading to increased myocardial stiffness and reduced compliance [84, 85]. Furthermore, both conditions are associated with systemic and myocardial inflammation, which may synergize with CMD to promote HFpEF progression [86, 87].

Therapeutic Strategies Targeting Inflammation and CMD in HFpEF

Chronic low-grade inflammation and CMD are now recognized as central drivers of HFpEF pathogenesis. As a result, targeting inflammation, oxidative stress, and impaired endothelial signaling has emerged as a promising strategy. In the D-HART pilot trial, the IL-1β antagonist anakinra significantly reduced CRP levels and improved aerobic capacity in HFpEF patients [88]. Similarly, anti-IL-6 receptor antibodies modulated ECM remodeling and titin phosphorylation in a viral myocarditis mouse model, demonstrating cardioprotective effects [89]. Beyond lipid lowering, statins improve HFpEF outcomes by attenuating inflammation, reducing myocardial nitrotyrosine, enhancing PKG activity, and improving myocardial compliance [10, 90, 91]. The NLRP3 inflammasome, activated by sterile and non-sterile insults, contributes to HFpEF pathogenesis [92]. Inhibiting NLRP3 reduces cardiac remodeling, hypertrophy, fibrosis, and inflammation in HFpEF [93, 94].

Cardiac fibrosis, hypertrophy, and cardiomyocyte stiffness in HFpEF are closely associated with impaired NO-sGC-cGMP-PKG pathway, making it a promising therapeutic target. Inflammation and oxidative stress reduce NO bioavailability in ECs and cardiomyocytes, which may be counteracted by NO donors (e.g., nitrates) to restore NO balance. However, organic nitrates like isosorbide mononitrate are limited by their ability to increase ROS production, worsening endothelial dysfunction and reducing exercise capacity in HFpEF patients [95]. In contrast, inorganic nitrates such as nitrite precursors, which preferentially reduce to NO during hypoxia and acidosis, are under investigation for their potential in HFpEF [96]. Intravenous sodium nitrite has been shown to reduce exercise-induced pulmonary capillary wedge pressure, improve cardiac output, and enhance exercise capacity [97].

Phosphodiesterase inhibitors, particularly PDE5 and PDE9 inhibitors, may also improve cGMP levels in cardiomyocytes, thereby enhancing the NO signaling pathway [96]. For example, sildenafil has been demonstrated to improve diastolic function and exercise capacity in HFpEF patients and pulmonary hypertension [98]. sGC stimulators, such as BAY 41-8543, have also shown promise in enhancing NO signaling in HFpEF rats by improving endothelial function, reducing inflammation and fibrosis, and attenuating cardiac remodeling [99]. The SOCRATES-PRESERVED trial investigated vericiguat, an sGC stimulator, and although it did not significantly change NT-proBNP levels or left atrial size, it was well tolerated and improved the quality of life in HFpEF patients [100].

SGLT2 inhibitors, beyond their glycemic effects, have been shown to improve outcomes in HFpEF patients by reducing myocardial inflammation and oxidative stress, enhancing NO-sGC-cGMP signaling, and reducing cardiomyocyte stiffness [101]. Empagliflozin has been shown to inhibit the expression of ICAM1, VCAM1, TNF-α, and IL-6, improve endothelial function, and reduce oxidative stress and inflammation in human and rat HFpEF myocardium, which collectively leads to improved myocardial compliance [102, 103].

Additionally, ET-1 is closely associated with endothelial dysfunction, cardiac hypertrophy, and fibrosis in HFpEF. ET-1 receptor antagonists have demonstrated beneficial effects on cardiac remodeling in HFpEF. For instance, macitentan, a dual ET-A/ET-B receptor antagonist, reduced cardiomyocyte hypertrophy, collagen I deposition, and titin N2B expression in mice with HFpEF [104]. A summary of completed and ongoing clinical trials targeting inflammation in HFpEF is provided in Table 2.

Summary and Future Perspectives

HF represents a major global public health challenge. With increasing life expectancy and changes in dietary patterns, living environments, and other factors, the prevalence of chronic multisystem and metabolic-associated diseases is rising, contributing to a higher incidence of HFpEF. This review has discussed the role of inflammation, CMD, and HFpEF pathophysiology and outlined current therapeutic strategies targeting these pathways. However, the mechanisms of HFpEF are multifactorial and extend beyond inflammation and CMD. Future research should not only focus on the heart but also integrate the broader context of systemic lesions. Utilizing bioinformatics and multimodal imaging technologies to explore these mechanisms could facilitate the identification of more specific biomarkers and diagnostic indicators. This would enable earlier detection of high-risk patients, improving outcomes by preventing the onset of HFpEF.

Statement of Ethics

An ethics statement is not applicable because this narrative review is based exclusively on the published literature.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study is supported by the Natural Science Foundation of Gansu Province (Grant No. 23JRRA1608) and Fund of the First Hospital of Lanzhou University (Grant No. ldyyyn2022-46).

Author Contributions

Xiaoli Yan, Ruxia Wang, and Hui Xu made substantial contributions to the conception or design of the work. Xiaoli Yan and Ruxia Wang wrote the original draft. Zhongbin Tao and Jizu Ling reviewed and edited the manuscript. All authors read and approved the final manuscript.