Review Article

Unravelling the Pathogenesis of Heart Failure with Preserved Ejection Fraction: The Pivotal Role of Autophagy and Endoplasmic Reticulum Stress

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Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and is associated with high morbidity and mortality. Despite its prevalence, effective therapies remain elusive due to its complex and multifactorial pathophysiology, including systemic inflammation, microvascular dysfunction, myocardial fibrosis and diastolic dysfunction. Recent evidence has highlighted the central role of cellular stress responses (particularly autophagy and endoplasmic reticulum stress) in the progression of HFpEF. This review examines current evidence on the roles of autophagy and endoplasmic reticulum stress in HFpEF, focusing on their interplay and associated biomarkers, including light chain 3 (LC3), Beclin-1, GRP78 and CHOP. Dysregulated autophagy and endoplasmic reticulum stress have been shown to promote vascular senescence, inflammation, fibrosis and further remodelling in HFpEF. The targeting of autophagy and endoplasmic reticulum stress offers new diagnostic and therapeutic avenues. Future research should prioritise biomarker development and personalised therapies to shift HFpEF management from symptom control to molecular targeting.

Keywords

Autophagy, endoplasmic reticulum stress, heart failure with preserved ejection fraction, pathogenesis, cardiovascular diseases,

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DOI: https://doi.org/10.15420/ecr.2025.50

Disclosure: The authors have no conflicts of interest to declare.

Correspondence: Citrawati Dyah Kencono Wungu, Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Jl. Prof. Dr Moestopo No. 47, Surabaya, Indonesia 60132. E: citrawati.dyah@fk.unair.ac.id

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© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure with preserved ejection fraction (HFpEF) is a multifaceted and multifactorial syndrome defined by symptomatic heart failure (HF) with left ventricular ejection fraction (LVEF) ≥50%.1 HFpEF is a significant global health concern due to its high comorbidity burden, particularly in older people. It now accounts for more than half of all HF cases and the proportion is continuing to increase.2 Despite its increasing prevalence and poor prognosis, therapeutic strategies for HFpEF remain limited and mostly ineffective.3

Due to its complicated and frequently overlapping clinical presentation, HFpEF is underdiagnosed, particularly in the early stages, and can be mistaken for other conditions.4 Cardiovascular and non-cardiovascular comorbidities and risk factors complicate diagnosis and treatment, and pathophysiological factors are thought to play a major role in the high burden of comorbidities involved in HFpEF.2

Understanding of the pathophysiology of the underlying molecular mechanisms is important to increase diagnostic and therapeutic strategies for HFpEF. Numerous studies have demonstrated the crucial roles that endoplasmic reticulum (ER) stress and autophagy dysfunction play in the pathophysiology of HFpEF, and have highlighted these pathways as important mediators of systemic inflammation and cardiomyocyte remodelling. However, the precise interplay between autophagy and ER stress is still to be fully elucidated.

This review aims to investigate the intertwining mechanisms involved in autophagy and ER stress and how their dysregulation may contribute to the onset and progression of HFpEF.

Pathophysiology of HFpEF

Initially, HFpEF was found to be an abnormality of the diastolic phase. The understanding of HFpEF has evolved into a more complex picture, in which HFpEF is a comorbidity-driven clinical syndrome.5 One of the most salient characteristics of HFpEF is diastolic dysfunction. Diastolic dysfunction is the impaired ability of the ventricle to fill with an acceptable preload volume at acceptably low filling pressures.6 However, diastolic dysfunction does not always indicate the presence of HFpEF in all patients; rather, it indicates only abnormal mechanical ventricle function, regardless of the symptomatic status of the patient. Other cardiovascular abnormalities can also contribute to HFpEF, including mild left ventricular (LV) systolic dysfunction, left atrial impairment, increased pericardial restraint, pulmonary vascular disease and vascular stiffening.7

Diastolic dysfunction results from impaired calcium handling, reduced cellular energy, myocardial fibrosis and extracellular matrix remodelling, which stiffen the ventricle and raise left ventricular end-diastolic pressure (LVEDP). This elevated filling pressure is transmitted to the left atrium and pulmonary veins, causing pulmonary congestion and reducing the heart’s pumping efficiency despite a preserved ejection fraction.7

HFpEF is no longer seen as only a heart problem. Emerging evidence indicates that it is a complex condition that affects many organs, including the lungs, blood vessels, kidneys, fat tissue, and even muscle. Research indicates that HFpEF often develops due to a combination of other health issues, many of which do not directly involve the heart, including obesity, type 2 diabetes and metabolic syndrome.5 One of the key underlying mechanisms linking these comorbidities to HFpEF is chronic systemic inflammation.

Obesity is a central comorbidity in HFpEF, driving chronic inflammation, oxidative stress and pro-inflammatory adipokine release that adversely affect the heart and vasculature. It also promotes insulin resistance, lipid derangement and neurohormone activation, leading to LV hypertrophy, diastolic dysfunction and impaired myocardial energy metabolism. Together, these obesity-driven mechanisms critically contribute to the complex pathophysiology of HFpEF.8 Beyond systemic metabolic disturbances, cellular mechanisms, such as dysregulated autophagy and ER stress, also contribute to HFpEF. Autophagy works by eliminating damaged organelles, protein aggregates, and invading microorganisms to maintain cellular balance and provide essential nutrients. The size of cardiomyocytes and the functionality of the heart are affected by autophagy. The absence of autophagy in cardiomyocytes can result in cardiac hypertrophy, which further worsens HFpEF.9 In addition, dysregulated autophagy leads to vascular senescence, arterial stiffening and pathological cardiac remodelling.10 In contrast, ER stress arises due to the build-up of misfolded proteins. This triggers the unfolded protein response (UPR), a cellular response to restore normal function. The UPR initially responds to the increased stress in the ER by accommodating the protein-folding needs, resulting in ER expansion via sheet formation and expansion of the folding machinery. While UPR is adaptive in responding to ER stress, inadequate downregulation of ER stress and recovery of homeostasis can cause cell dysfunction and apoptosis.11,12 In HFpEF, these events are responsible for LV dysfunction and myocardial fibrosis. Modulating autophagy and ER stress to recover protein homeostasis can reduce cellular stress and improve heart function, offering promising therapeutic targets for the treatment of HFpEF.12

Autophagy of the heart can be triggered by various stimuli, with oxidative stress being one of the primary inducers. Elevated oxidative stress enables increased production and accumulation of lipid peroxidation byproducts, which in turn stimulate autophagic mechanisms as a cellular defence mechanism. It is influenced by ageing, genetic predisposition, conventional risk factors, and environmental influences. Obesity, a chronic inflammatory condition, is a significant contributor to oxidative stress. Adipocytes in obese individuals release pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6, which stimulate the production of reactive oxygen species (ROS) and nitric oxide synthase (NOS) in immune cells, thereby amplifying oxidative stress.13 Angiotensin II, secreted by adipose tissue, enhances nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and thereby promotes ROS. ROS, which are produced as byproducts of aerobic metabolism, play a pivotal role in the development of HF.14

An imbalance between the production of ROS and protection by antioxidants may initiate oxidative stress. Therefore, mitochondrial component oxidation and augmentation of hydrogen peroxide (H2O2) lead to endothelial and contractile dysfunction, arrhythmia, hypertrophy and pathological remodelling of cardiomyocytes.14 ROS then disrupts nitric oxide (NO) signalling, leading to the build-up of collagen and other extracellular matrix components, which increase myocardial stiffness and diastolic dysfunction. ROS also induce lipid peroxidation in cellular membranes, disrupting mitochondrial integrity, which facilitates cellular apoptosis. Ultimately, ROS also disturb sodium and potassium balance, which can lead to arrhythmias.15

Understanding the intricate relationship between metabolic dysregulation, inflammation, oxidative stress and cellular stress mechanisms, such as autophagy and ER stress, is important for developing a more effective therapy for HFpEF. Ongoing research into novel molecular targets involved in cellular stress responses and identification of more precise biomarkers for patient stratification are crucial for advancing the treatment of this complex and increasingly prevalent disease. Given the complex interplay between metabolic stress, inflammation and cellular homeostasis, particular attention has been directed toward the role of autophagy dysregulation in HFpEF.

Autophagy Dysregulation in the Pathogenesis of HFpEF

Autophagy is a conserved catabolic process that plays a crucial role in maintaining normal cellular homeostasis under cellular stress. In response to various cellular stressors, including ischaemia, mechanical and oxidative stress, inflammation, starvation and ER stress, a lysosomal degradation process is activated to maintain cellular homeostasis. This process is known as autophagy. The activation of autophagy is tightly regulated by complex signalling pathways present in stressful or ROS-rich environments.10 It serves as a quality control mechanism by removing damaged proteins and organelles.16 To meet energy demand and improve cellular survival, autophagy can provide energy and materials for protein synthesis and biofilm in nutrient scarcity by breaking down damaged organelles and preventing cell apoptosis. This process is especially crucial in the onset and progression of cardiovascular diseases.17

There are three primary types of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA).18 Macroautophagy, often simply called autophagy, is characterised by the formation of a distinctive double-membrane vesicle known as the autophagosome and is the most significant. In contrast, microautophagy entails the direct invagination of the lysosomal membrane to assimilate cytoplasmic material, whereas CMA is distinct in that it does not involve membrane restructuring. Instead, CMA functions through a selective process facilitated by the chaperone hsc70, along with co-chaperones and the lysosomal receptor LAMP-2A (lysosomal-associated membrane protein type 2A).18

In the proteolytic process, improperly folded proteins will undergo ubiquitination and be detected by the p62 (sequestosome 1) protein (Figure 1). Encoded by the SQSTM1 gene, p62 is an autophagy substrate used to measure autophagy activity, and it serves as a link to connect the ubiquitin–proteasome system (UPS) and autophagy pathways. It has recently been demonstrated that p62 transports ubiquitinated proteins to the proteasome for destruction. When UPS is inhibited, p62 is upregulated and phosphorylated, further activating the autophagy pathway.19

Figure 1: Schematic View of the Autophagy Process

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Autophagy starts with the formation of a phagophore (a transient double-membrane structure) or isolation membrane. It plays an active role in the formation of sequestosomes (a structure for cytoplasm sequestration). The autophagosome is complex molecular machinery consisting of more than 30 autophagy-related (ATG) proteins and 50 lysosomal hydrolases. Later, the autophagosome fuses with the lysosome and its cargo is degraded by proteases and other lysosomal enzymes. In addition to providing cells with essential nutrients, this process plays a critical role in maintaining cellular homeostasis by removing damaged or excess organelles, protein aggregates and invading microbes, directing them to the lysosomes for degradation.10

The autophagy process involves the activation of many proteins. The initiation of autophagy begins with activation of the ULK1/ATG1 complex, a process tightly regulated by mTORC1 and AMP-activated protein kinase (AMPK). The complex subsequently stimulates the class III PI3K complex (comprising PI3K, Beclin-1, VPS15 and other partners) to drive autophagosome nucleation. Beclin-1 functions as a central scaffold at this stage, recruiting key regulators, such as ATG14L, activating molecule in Beclin 1-regulated autophagy (AMBRA1), UV radiation resistance-associated gene (UVRAG), and Rubicon to modulate PI3K lipid kinase activity and coordinate the formation of the autophagosomal membrane.20

Normal autophagy levels are essential to maintain cardiac function, but when autophagy becomes excessive or dysregulated, it can harm the heart. Recent evidence emphasises the importance of autophagy dysregulation in the pathogenesis of HFpEF. At moderate levels, autophagy is cytoprotective and essential to maintaining cellular homeostasis, but excessive or decreased autophagic activity can be detrimental and may contribute to cell death.21

Dysregulation of autophagy, particularly in the vascular compartment, has been linked to vascular senescence and the progression of HFpEF.22 As a key intracellular degradation pathway, autophagy normally acts to restrain cardiomyocyte hypertrophy. However, when excessive, it can drive uncontrolled protein breakdown, culminating in severe cardiac atrophy. Moreover, sustained autophagic activation has been implicated in maladaptive remodelling, thereby promoting pathological hypertrophy and the progression of HF.23 Depending on the context of the stressor and the stage of disease progression, this dysregulation condition can have both adaptive and maladaptive consequences.21 Enforcing the role of autophagy, inflammation plays a central role in the pathophysiology of HFpEF, distinguishing it from HF with reduced ejection fraction (HFrEF). This suggests that autophagy markers may have potential diagnostic value in differentiating between HF subtypes and assessing severity.

Autophagy-induced vascular senescence plays a critical role in the development of HFpEF, due to its contribution to key features of the disease, such as vascular stiffening and endothelial dysfunction.22 The evidence of increased expression of autophagy biomarkers, such as MAP1LC3, Beclin-1 and p62 in diabetic myocardium suggests their role in metabolic and cardiac dysfunction.24 RNA sequencing analysis in patients with HFpEF showed that genes related to ER stress, angiogenesis and autophagy are related to the progression of HFpEF.25 The autophagic markers MAP1LC3 and p62 have also been proposed as potential diagnostic tools for drug-induced autophagic vacuolar cardiomyopathy, a histological finding not uncommonly found in HF.26 Moreover, MAP1LC3B was known to have protective effects in models of pulmonary hypertension, suggesting that modulation of autophagy could offer therapeutic benefits in cardiovascular diseases.16 However, the regulation of these markers varies across different tissues in preclinical models of HF, highlighting the complexity of autophagic regulation in HFpEF.27 Another autophagy protein, ATG7, also plays a crucial role in heart metabolism. ATG7 is a crucial component that initiates the classic autophagy mechanism through the formation and expansion of autophagosome membranes. ATG7 also plays important roles in protein lipidation events similar to ubiquitination and membrane fusion events during autophagy. ATG7 could activate TAT-Beclin-1, a peptide derived from a region of Beclin-1 protein, which has a cardioprotective effect.28

Interestingly, some studies have shown that autophagy inhibition can attenuate cell death in specific contexts, indicating that heightened autophagic activity may become maladaptive. Indeed, excessive autophagy can trigger a unique form of programmed cell death, known as autosis, which is characterised by distinct morphological and biochemical hallmarks.23 Autosis is a recently recognised form of cell death distinct from apoptosis and necrosis, marked by excessive accumulation of autophagosomes that ultimately damage cardiomyocytes. Although the role of autophagy in HF remains complex, excessive autosis during advanced stages of HF and ischaemia–reperfusion injury has been shown to exacerbate cardiac dysfunction by impairing cellular integrity and promoting cell loss. Consequently, targeting autosis represents a promising therapeutic approach to mitigate myocardial injury in these settings.20

Intriguingly, autophagy is also influenced by circadian rhythm. Activation of the transcription factor circadian locomotor output cycles kaput (CLOCK) enhances the expression of essential autophagy-related genes, including ATG7, Tfeb, Sqstm1/p62 and Rab7a. Conversely, CLOCK gene silencing suppresses these autophagy regulators and heightens vulnerability to cardiac stress.29 Another critical regulator, REV-ERBα, further links autophagy to circadian control. In line with this, Montaigne et al. demonstrated that pharmacological inhibition or genetic deletion of REV-ERBα mitigated cardiac injury during the sleep–wake transition, an effect associated with upregulation of the cell cycle regulator CDKN1a/p21.30

Although dysregulated autophagy is central to HFpEF, it operates as part of a broader network of cellular stress responses. One of the most closely connected pathways is ER stress, which can be triggered by the same insults that disrupt autophagy, such as metabolic imbalance, oxidative stress and inflammation. The relationship between ER stress and autophagy is bidirectional: accumulation of misfolded proteins in the ER activates the UPR, which, in turn, induces autophagy to help remove these proteins and damaged cellular components. At the same time, autophagy supports cellular recovery by reducing the burden of misfolded proteins and dysfunctional organelles, thereby relieving ER stress.31 Thus, understanding ER stress in the context of HFpEF offers a complementary perspective on how interconnected stress pathways drive disease progression.

Endoplasmic Reticulum Stress in HFpEF

ER stress arises when misfolded proteins accumulate in the ER, activating the UPR through three main signalling pathways: ATF6, IRE1α and PERK (Figure 2 ). These pathways work to mitigate stress by enhancing protein folding capacity, lipid metabolism and calcium homeostasis in cardiomyocytes. This results in the upregulation of genes encoding ER chaperones and components of ER-associated degradation genes.32 This adaptive response is necessary for maintaining cellular function under stress. Still, it can lead to apoptosis in a prolonged or unresolved condition, which contributes to the progression of cardiovascular diseases, including cardiac hypertrophy in HF.33 ER stress can be triggered by ischaemia, reperfusion injury, oxidative stress, hypertrophy-induced protein synthesis overload and increased metabolic demand.29

Figure 2: Endoplasmic Reticulum Stress Pathway

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ER stress has been implicated in the pathogenesis of HFpEF, a condition characterised by diastolic dysfunction and cardiac remodelling.30 Markers of ER stress, including GRP78, CHOP, DDIT3, ATF6 and IRE1α, are overexpressed in both animal models and humans with HFpEF, reflecting the occurring cellular stress response.31 Recently, the significance of ER stress markers in the monitoring and diagnosis of HFpEF has garnered attention, with GRP78, CHOP and caspase-3 emerging as promising indicators of disease severity and prognosis. Elevated expression of GRP78 and caspase-3 has been demonstrated in patients with HFpEF.34 GRP78 is a major chaperone involved in protein folding, apoptosis regulation against ER stress-induced cell death, and activation of downstream signalling pathways to restore cellular homeostasis under stress conditions. At the same time, caspase-3 is a protease with an essential proteolytic function that orchestrates programmed cell death as a target control for apoptosis.35 These biomarkers of autophagy and ER stress not only indicate cellular damage, but also correlate with increased inflammation and worsened cardiac function.

Chronic inflammation in HFpEF imposes prolonged stress on cardiomyocytes. When the UPR pathway fails to cope with the accumulation of unfolded proteins, it can further increase the production of ROS and mitochondrial dysfunction. This chronic inflammation also activates fibrosis, a hallmark of HFpEF, through dysregulated accumulation of extracellular matrix proteins.36 In addition, inflammation is a critical mediator of disease progression in HFpEF, and ER stress exacerbates this process by enhancing the activation of pro-inflammatory cytokines, including TNF-α, IL-6 and IL-1β. These cytokines could further drive endothelial dysfunction and vascular remodelling or stiffening as the main contributors to compromised diastolic function typically found in HFpEF patients.37

ER stress contributes to hypertension by upregulating NADPH oxidase (NOX)4 in vascular smooth muscle cells (VSMCs), as heightened NOX activity promotes vascular oxidative stress in this condition.38 Additionally, protein-folding chaperones in the ER are also upregulated, such as GRP78, calnexin and calreticulin, which function as Ca2+-binding proteins to help maintain Ca2+ concentration. However, under ER stress, Ca2+ leakage from the ER lumen into the cytosol may disrupt cholesterol and calcium regulation and thereby contribute to various metabolic and cardiovascular disorders, including hypertension.39

Modulating ER stress, particularly through the CHOP pathway, shows promise in animal models against HFpEF conditions. By attenuating harmful effects and preventing disease development, the targeting of UPR approaches could offer new treatment possibilities in HFpEF.30 Similarly, pharmacological agents that target specific UPR components, such as inhibitors of IRE1α or PERK, have shown potential in reducing ER stress and mitigating myocardial inflammation in experimental HF models.40

A study by Zhang et al. focused on Pak2, which promotes a protective ER stress response in a mouse model of HFpEF.41 Some natural products were also shown to decrease ER stress markers, such as GRP78, CHOP, PERK and IRE1α in various cardiovascular disease models, either in vitro or in vivo.42 In human studies, the anti-anginal drug nicorandil has been shown to markedly decrease the expression levels of GRP78, CHOP and ER stress markers in atherosclerotic lesions.43 Despite promising developments, therapeutic options for HFpEF via ER stress pathways remain limited, and the differences between animal and human models in reflecting HFpEF still pose a challenge to determining whether therapeutic approaches can truly benefit HFpEF patients (Supplementary Table 1 ).

Autophagy and Endoplasmic Reticulum Stress in HFpEF

Autophagy and ER stress are interconnected cellular mechanisms that play essential roles in maintaining cellular homeostasis under stress conditions. When ER stress occurs, it can trigger the UPR pathway aimed at restoring protein-folding capacity and cellular function, which later activates the autophagy mechanism. This process includes transcriptional activation of autophagic proteins driven by CHOP or PERK-eukaryotic initiation factor 2 α (eIF2α) signalling pathway to initiate apoptosis. Additionally, ER stress signalling has been shown to promote the production of Beclin-1 and ATG while inhibiting the ability of rapamycin kinase complex 1 to activate autophagy.44 ER stress both promotes and suppresses autophagic processes, depending on the context and severity of the stress.45

Both autophagy and ER stress rely on overlapping signalling pathways, including key components such as PERK/ATF4, IRE1α, ATF6 and Ca2+ signalling.46 One critical mediator in this interaction is the mTOR pathway, which modulates both upstream and downstream ER stress signals and integrates these cellular responses to stress.10 Another mediator is HHATL, which ameliorates ER stress and protects cells by promoting autophagy through interaction with the autophagic protein LC3 via the LC3-interacting region (LIR) motif.44 Here, autophagy serves a protective role by maintaining cellular integrity, often by inhibiting caspase activation, a key mediator of apoptosis. However, excessive or dysregulated autophagy may lead to cell death, underscoring the crucial balance between cell survival and apoptosis.46

The disarrangement of the interrelationship between ER stress and autophagy has been implicated in several diseases, such as autoimmune disorders, in which their interaction affects T-cell activity and inflammation.47 They are also involved in ageing-related diseases given that their imbalance is crucial in cell senescence.22 In the context of cardiovascular diseases, the relationship between ER stress, autophagy and apoptosis becomes particularly relevant. Autophagy is essential to counteract the negative effects of ageing on the heart. Accumulation of oxidative stress, mitochondrial or DNA damage, proteotoxicity, inflammation/inflammageing and cellular senescence due to the disruption between the autophagy and ER stress pathway could lead to vascular damage. This could lead to several cardiovascular diseases, including atherosclerosis, hypertension, cardiac hypertrophy and HF.48

In HFpEF, ER stress and autophagy significantly contribute to vascular senescence and arterial stiffness. Additionally, the integrated ER stress response coordinates autophagy alongside other cellular stress responses, enabling cells to adapt to varying conditions.49 However, when this response becomes overwhelmed or dysregulated, it can transition from a protective mechanism to a maladaptive one, resulting in cardiomyocyte death and fibrosis, the hallmarks of HFpEF pathology.

Prospective Trajectories in HFpEF

Although there has been significant progress in understanding the pathophysiology of HFpEF, further research focusing on the long-term effects of modulating autophagy and ER stress is needed. Most existing studies were conducted on animal models, highlighting the need for future human research. HFpEF is a highly heterogeneous disease, which has contributed to the largely unsatisfactory outcomes of clinical trials investigating potential treatments. This suggests that a one-size-fits-all approach is ineffective for managing HFpEF. Tailoring treatments to the specific phenotypes of the disease may lead to better outcomes. Ongoing research into the diverse characteristics of HFpEF will be vital for developing more personalised and effective management strategies.50

Imaging modalities and functional assessment are the primary components of current diagnostic techniques in HFpEF. Although imaging techniques are still necessary for the visualisation of cardiac structure and function, they frequently fail to detect cellular changes in the initial stages. The integration of autophagy and ER stress biomarkers provides a complementary approach for the early detection of HF. Several biomarkers of autophagy and ER stress have been further studied in other clinical cases as diagnostic markers, for instance, Beclin-1 and LC3, which have been widely used as biomarkers for autophagy. They could also be used as prognostic biomarkers for colorectal carcinoma, with remarkable sensitivity and specificity to predict metastasis.51 Another study also showed that the expression of LC3-II was increased, while the p62 level and Beclin-1 expression were decreased in melanoma. However, most studies investigating these biomarkers in clinical settings have been conducted in the context of malignancy. A study by Zhao et al. investigated GRP78, caspase-3 and CHOP levels for diagnostic accuracy and prediction of mortality in HF, which showed promising results.52 Nevertheless, the diagnosis accuracy analysis in that study did not separate the results between HFrEF and HFpEF.

Even though these biomarkers have the potential to facilitate earlier intervention and improved patient outcomes by providing insights into the molecular and cellular changes that occur prior to the detection of substantial structural alterations on imaging, more studies are needed to confirm the results, specifically in the setting of HFpEF. In addition to early diagnosis, biomarker analysis can also serve as an indicator of therapeutic efficacy and recovery.53

Potential Therapeutic Strategies in HFpEF

The clinical significance of investigating and targeting therapy for autophagy, ER stress and oxidative stress in HFpEF is gaining increasing attention. A growing number of clinical trials investigating therapies to improve autophagic function or diminish ER stress suggest that the integration of these approaches into standard HFpEF care may soon be feasible. Developments in gene therapy, small-molecule inhibitors, and other targeted medicines may revolutionise the management of HFpEF by enabling the modulation of biological processes. Currently, research into the use of autophagy modulation modalities and ER stress targeted therapy in the treatment of malignancy and neurodegenerative diseases is also being conducted, in addition to that in the cardiovascular field.54 Moreover, an expanding body of research supports the potential of targeting autophagy, ER stress and oxidative stress as novel therapeutic approaches specifically tailored to the pathophysiology of HFpEF.

Modulating Autophagy for HFpEF Treatment

Regulating autophagy to achieve normal physiological balance may offer protection to cardiomyocytes and vascular cells against maladaptive remodelling and cellular senescence. Enhancing autophagy can eliminate impaired organelles and atypical protein aggregates, which in turn protects the function of cardiomyocytes, sustains intracellular equilibrium, and represents a promising treatment strategy for HFpEF.54

Previous studies have explored the therapeutic potential of schaftoside, a flavonoid compound derived from Grona styracifolia. Schaftoside plays a crucial role in activating cellular autophagic processes, which improves diastolic function in HFpEF by modulating the autophagy–lysosome pathway through allosteric inhibition of CaMKII-δ.55

Metformin has shown notable potential as an autophagy modulator across various disease models through its effect by activating the AMPK–mTOR signalling pathway, which promotes autophagy in several cell types and ultimately improves metabolic dysfunction and inflammation in HFpEF patients. Research has demonstrated that metformin enhances AMPK phosphorylation while decreasing mTOR phosphorylation, leading to increased levels of autophagy indicators such as LC3-II and reduced levels of p62: markers that reflect enhanced autophagic activity.56 Beyond its anticancer properties, metformin-induced autophagy contributes to better energy metabolism and offers protective effects supporting ATP production and cell survival under stress, especially in HF.57

In addition to metformin, other pharmacological agents such as rapamycin have demonstrated potential in restoring autophagic balance and enhancing cardiac performance in HFpEF. Rapamycin acts as a potent mTOR inhibitor that stimulates autophagy by inhibiting mTORC1, negatively regulating autophagy.58 In addition to this classical pathway, rapamycin has also been shown to activate MEK/ERK signalling, which upregulates autophagy-related proteins such as Beclin-1 and Noxa.59 By decreasing mTORC1 activity, rapamycin promotes the development of autophagosomes, thereby improving the removal of dysfunctional organelles and protein aggregates.58 In HFpEF, this restoration of autophagic activity has exhibited cardioprotective benefits, such as diminished myocardial fibrosis and enhanced diastolic function. Furthermore, preclinical investigations have indicated that rapamycin reduces pathological hypertrophy, enhances ventricular compliance and reverses adverse remodelling.60

Beyond their well-known lipid-lowering effects, statins have emerged as autophagy modulators through diverse molecular mechanisms, which may promote their cardioprotective properties, especially in HFpEF. Simvastatin has been shown to promote autophagosome formation and enhance autophagosome–lysosome fusion in coronary arterial myocytes: effects that are diminished by Rac1 overexpression or mTOR activation, which highlights the importance of the Rac1-mTOR axis in statin-induced autophagy.

Additionally, statins can also stimulate autophagy via pathways involving sirtuin (SIRT)1, p21, nuclear p53 and LKB1-AMPK.61 Atorvastatin has been found to boost autophagy in non-ischaemic cardiac tissue by inhibiting mTOR and reducing p62 build-up. There is also strong evidence indicating that simvastatin mitigates excessive autophagy and restores the levels of 14-3-3 protein, a highly conserved regulatory protein involved in a wide range of cellular processes, by reducing LC3-I/LC3-II, thereby protecting cardiomyocytes against hypertrophy.62 These autophagy-related actions help preserve cardiovascular structure and function, positioning statins as potential therapeutic agents in HFpEF beyond their traditional role in lipid regulation.

Other drugs, including chloramphenicol and sulfaphenazole, also activate autophagy, contributing to their protective effects against ischaemia–reperfusion injury and other conditions. Sodium–glucose cotransporter 2 inhibitors have shown benefits in HF by triggering autophagy and reducing cardiovascular mortality. Unfortunately, none of these drugs selectively targets the autophagy pathway. Instead, they influence multiple cellular processes, making it challenging to determine which specific pathway is responsible for the desired protective effect.10,63

Alleviating Endoplasmic Reticulum Stress

Emerging pharmacological agents that target the UPR are being recognised as valuable strategies for the treatment of cardiovascular diseases. Evidence suggests that salubrinal, which inhibits eIF2α phosphatase, significantly elevates GRP78 levels and appears to safeguard cardiomyocytes from apoptosis caused by ER stress in a rat MI model.64 Resveratrol, an antioxidant, is the most potent SIRT1 activator to prevent ER stress-induced apoptosis and improve cardiac function in cardiomyocytes through eIF2α deacetylation, highlighting the therapeutic potential of SIRT1 activators in addressing cardiac disorders linked to ER stress.65 Moreover, the reduction of ER stress can be facilitated by using chemical chaperones that imitate ER chaperones to stabilise and rescue misfolded proteins, in conjunction with an increased expression of CHOP, which is present in hearts undergoing pressure overload.11

Atorvastatin has demonstrated protective effects in post-MI HF models by reducing cardiomyocyte apoptosis by downregulating ER stress markers such as caspase-12 and CHOP.53 Angiotensin II type 1 receptor blockers, such as telmisartan and olmesartan, have been shown in preclinical studies to attenuate cardiac hypertrophy by suppressing ER stress-mediated apoptosis, notably through decreased expression of GRP78, CHOP, caspase-12 and phosphorylated c-Jun N-terminal kinase (JNK).66 Vitamin D receptor agonists, including calcitriol and paricalcitol, exhibit cardioprotective effects in ischaemia–reperfusion injury by inhibiting key apoptotic mediators such as CHOP and caspase-12.67 These findings highlight the therapeutic potential of targeting ER stress-induced apoptosis in pressure-overloaded cardiac conditions, such as HF.

Recent research by Zhang et al. has identified that Pak2 plays a significant protective role against ER stress in HFpEF, suggesting that targeting Pak2 could have therapeutic potential.41 The authors found that Pak2 deficiency exacerbates ER stress and inflammation, worsening cardiac function in HFpEF models. Conversely, restoring Pak2 activity helps suppress ER stress via inhibition of the IRE1α-XBP1 pathway, reducing fibrosis and improving diastolic function.41 Pak2 has been shown to facilitate a protective ER stress response, preventing HFpEF progression through cardioprotective effects against ER stress, suggesting that Pak2 modulation is a promising strategy for mitigating ER stress and treating HFpEF.69

Binder et al. highlighted that Pak2 is a crucial regulator of the protective role against ER stress under pressure overload through a catalytic subunit of a PP2Ac (protein phosphatase 2A)-dependent mechanism.68 Pak2 exerts cardioprotective effects by enhancing adaptive ER stress responses and suppressing pathological inflammation. In animal models, Pak2 deficiency has been shown to worsen ER stress via overactivation of the IRE1 phosphorylation and XBP1s pathway, leading to increased fibrosis, inflammation and impaired diastolic function.41 Restoring Pak2 activity reversed these effects, suggesting that Pak2 modulation could be a novel and effective therapeutic strategy to attenuate ER stress and improve outcomes in HFpEF.

Other Potential Therapeutic Strategies

Novel HFpEF therapies include endothelial nitric oxide synthase (eNOS) activators, matrix metalloproteinase 9 (MMP-9) inhibitors, and the investigation of current inhibitors, such as sacubitril/valsartan (formerly LCZ696) and spironolactone, which are undergoing clinical trials.69 New treatment approaches that target endothelial dysfunction, systemic inflammation and cardiometabolic abnormalities look promising for HFpEF outcomes.70 There are also ongoing studies investigating therapies that target pulmonary hypertension, left atrial hypertension, fibrosis and plasma volume expansion with various modalities, from pharmacotherapies to cardiosphere-derived cell therapy.71

Therapies that showed promising results in HFrEF did not demonstrate similar benefits in HFpEF. A meta-analysis by Zhuang et al. found that sildenafil significantly improved the haemodynamic parameter peak VO₂ in HFrEF patients, but not in those with HFpEF.72 Spermidine, a natural polyamine, plays a cardioprotective role in HFpEF therapy, primarily by stimulating autophagy and mitophagy in cardiomyocytes. This enhanced autophagic flux improves mitochondrial function, reduces cardiac hypertrophy and preserves diastolic function, which is not seen in autophagy-deficient models, indicating that the therapeutic benefits of spermidine are autophagy dependent.73

Recently, a combination of chimeric antigen receptors T (CAR-T) cell therapy and epigenetic modifiers is becoming a promising therapy to relieve activation and subsequent fibrosis in HF. Immunotherapy with regulatory T cells (Tregs) could also become an option given that the number and function of Tregs are reduced in patients with HFpEF, with the extent of this impairment being associated with the severity of the HF phenotype, as well as increased rates of hospitalisation and mortality.74

Some of the autophagy and ER stress biomarkers could provide valuable information about myocardial stress responses, autophagic flux and apoptosis in HFpEF. While biomarkers such as p62 and LC3 are extensively used in research settings to assess autophagic flux, they cannot be used in the clinic due to tissue/context dependency and lack of standardised assays.24,25 Similarly, GRP78/BiP and CHOP are pioneering markers for ER stress, but lack specificity because they are induced in a number of diseases other than HFpEF.64,66 ATG7 shows therapeutic potential in preclinical models but lacks standard clinical assays.75 While promising, the clinical use of these biomarkers is limited by problems of non-specificity, heterogeneity and a need for further validation, with calls for standardised protocols to better implement these markers in the clinic. Supplementary Table 2 not only highlights the potential for these biomarkers to transform HFpEF diagnosis, but also the need for further clinical validation and standardisation. We summarise the overall pathogenesis and clinical relevance of these biomarkers in Figure 3.

Figure 3: Heart Failure with Preserved Ejection Fraction Pathways Linking Autophagy and Endoplasmic Reticulum Stress to Therapeutic Targets

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Limitations and Future Direction

Current research on autophagy and ER stress in HFpEF is constrained by several limitations. Much of the evidence is derived from preclinical models or small patient cohorts that often lack longitudinal follow-up. Heterogeneity in experimental designs, patient populations and biomarker assays hampers comparability across studies. Furthermore, insights from animal models may not fully translate to human pathology. Well-designed, multicentre clinical trials with standardised biomarker measurement protocols are urgently needed to clarify the prognostic and therapeutic value of these pathways in HFpEF. Nevertheless, targeting autophagy and the ER stress pathway offers a novel and promising approach for pharmacological treatment development. New therapeutic targets for HFpEF are becoming clearer as research continues to identify specific signalling networks that control these cellular mechanisms. Modulating autophagy or alleviating ER stress has the potential to reduce cellular damage, prevent disease progression and eventually improve patient outcomes. Although preclinical models provide invaluable insights, additional research is important to apply these findings in clinical settings.

Conclusion

Autophagy and ER stress play crucial roles in the pathophysiology and progression of HFpEF. An imbalance in this pathway may contribute to cellular damage, inflammation, oxidative stress, and fibrosis, ultimately leading to myocardial dysfunction in HFpEF. Understanding the roles of autophagy and ER stress in HFpEF has profound implications for both research and clinical practice. Insight into these processes could pave the way for the development of promising therapies that target the underlying cellular dysfunctions, rather than merely alleviating symptoms. Nonetheless, several issues must be addressed in future, including the complexity of the pathway, which makes the selection of preferred biomarkers challenging. In addition, the dynamic pathway makes it quite difficult to observe markers or administer therapy. Advancements in balancing ER stress, autophagy, and cell survival could lead to more effective, personalised strategies that ultimately improve the outcomes and quality of life of HFpEF patients.

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