Hyemin Kim

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome characterized by signs and symptoms of heart failure with a left ventricular ejection fraction ≥ 50%.^1,2 There are currently six million people diagnosed with heart failure in the United States, and HFpEF constitutes more than half of those diagnoses.^1,3,4 Moreover, its prevalence continues to rise due to an aging population and escalating metabolic disorders.¹ Unlike heart failure with reduced ejection fraction (HFrEF), the precise pathophysiological and molecular mechanisms driving HFpEF remain poorly understood, leading to a lack of targeted, effective therapies.^6,7 Historically viewed strictly as an isolated disorder of diastolic dysfunction, a recent paradigm shift conceptualizes HFpEF as a systemic syndrome fueled by a proinflammatory environment and metabolic dysregulation arising from comorbidities such as hypertension and obesity.^3,5 This chronic systemic inflammation drives severe molecular imbalances, most notably toxic nitrosative stress and a pathological surplus of nitric oxide (NO) across multiple organs.¹

Objective: In this narrative review, we sought to summarize contemporary scientific findings on the molecular role of NO imbalance in HFpEF pathogenesis and to examine what future therapies might look like.

Search Method: An online search of the PubMed database was conducted using the following keywords: “heart failure with preserved ejection fraction,” “nitrosative stress,” “nitric oxide,” and “S-nitrosylation.” Literature published after 2018 was considered.

Results: Preclinical models demonstrate that systemic inflammation upregulates inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS), generating a pathological surplus of NO and inducing a state of nitrosative stress.^5,6 This environment triggers excessive protein S-nitrosylation, which disrupts various vital cellular pathways.^5,6 Specifically, S-nitrosylation of the endonuclease inositol-requiring protein 1ɑ (IRE1ɑ) suppresses the generation of spliced X-box-binding protein 1 (XBP1s).⁶ Downregulation of the IRE1ɑ-XBP1s axis impairs protein quality control via the unfolded protein response.⁶ Additionally, endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2) is suppressed, leading to severe cardiac lipotoxicity and lipid metabolism dysregulation.⁸ Moreover, an imbalance between transnitrosylases and denitrosylases is created by the increased nitrosative stress, where common transnitrosylases like hemoglobin B (HBb) are upregulated while common denitrosylases like thioredoxin 2 (Trx2) and S-nitrosoglutathione reductase (GSNOR) are unchanged or downregulated.⁷ This imbalance was also found in the liver, kidney, and lungs of preclinical models, demonstrating the systemic, multiorgan nature of HFpEF.⁷ Translational data seem to validate these findings, showing elevated NOS2 and NOS1 transcripts in human heart tissue, as well as increased levels of transnitrosylases.^5-7 Finally, a recent study showed that combining the NO donor sodium nitrate with hydralazine, a peroxynitrite formation inhibitor, seems to neutralize the highly oxidative environment and improve diastolic function in preclinical models^.9

Conclusions: HFpEF is increasing in prevalence, now constituting more than half of the heart failure diagnoses in the United States.⁵ Recent studies suggest that it is not simply an issue of cardiac dysfunction; rather, it is a systemic syndrome involving NO imbalances, nitrosative stress, and subsequent S-nitrosylation of various proteins.^5-7 Thus, future combination therapies should aim to rectify NO bioavailability while simultaneously attenuating nitrosative and oxidative stress.⁹ It should be noted that, with continued research, new mechanisms and therapeutic targets will be identified to improve the health of patients with HFpEF.

Works Cited:

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
2. Redfield MM, Borlaug BA. Heart Failure With Preserved Ejection Fraction: A Review. 2023;329(10):827–838. doi:10.1001/jama.2023.2020
3. Campbell P, Rutten FH, Lee MM, Hawkins NM, Petrie MC. Heart failure with preserved ejection fraction: everything the clinician needs to know. Lancet. 2024;403(10431):1083-1092. doi:10.1016/S0140-6736(23)02756-3
4. Omote K, Verbrugge FH, Borlaug BA. Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies. Annu Rev Med. 2022;73:321-337. doi:10.1146/annurev-med-042220-022745
5. Yoon S, Kim M, Lee H, et al. S-Nitrosylation of Histone Deacetylase 2 by Neuronal Nitric Oxide Synthase as a Mechanism of Diastolic Dysfunction. Circulation. 2021;143(19):1912-1925. doi:10.1161/CIRCULATIONAHA.119.043578
6. Schiattarella GG, Altamirano F, Tong D, et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature. 2019;568(7752):351-356. doi:10.1038/s41586-019-1100-z
7. Li Z, LaPenna KB, Gehred ND, et al. Dysregulated Protein s-Nitrosylation Promotes Nitrosative Stress and Disease Progression in Heart Failure With Preserved Ejection Fraction. Circ Res. 2025;137(9):1185-1206. doi:10.1161/CIRCRESAHA.124.326042
8. Fonseka O, Raja R, Ross C, et al. XBP1s-EDEM2 Prevents the Onset and Development of HFpEF by Ameliorating Cardiac Lipotoxicity. Circulation. 2025;151(22):1583-1605. doi:10.1161/CIRCULATIONAHA.124.072194
9. LaPenna KB, Li Z, Doiron JE, et al. Combination Sodium Nitrite and Hydralazine Therapy Attenuates Heart Failure With Preserved Ejection Fraction Severity in a “2-Hit” Murine Model. J Am Heart Assoc. 2023;12(4):e028480. doi:10.1161/JAHA.122.028480