Heart Failure with Preserved Ejection Fraction: Challenges and Current Approaches
Abstract
Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with substantial morbidity, mortality, and impaired quality of life. Despite its rising prevalence, particularly among older adults and women, HFpEF has historically been characterized as a “therapeutic graveyard” because of decades of inconclusive or neutral clinical trials.
Methods: A secondary qualitative analysis of the literature indexed in PubMed, Scopus, and Embase from January 2018 through June 2025 was conducted. Randomized controlled trials, systematic reviews, meta-analyses, guideline statements, and high-quality observational studies were included. Data were extracted and synthesized thematically across five domains: epidemiology, pathophysiology, diagnostic strategies, therapeutic approaches, and future directions.
Results: Epidemiological data confirm increasing global prevalence, driven by aging demographics and clustering of comorbidities such as obesity, hypertension, diabetes, and atrial fibrillation. Pathophysiological insights highlight a complex, multiorgan syndrome with distinct phenotypes. Diagnostic accuracy remains hampered by overlapping comorbidities, limited biomarker sensitivity in obese or renally impaired patients, and heterogeneity in imaging findings. Artificial intelligence and machine learning approaches are emerging but not yet established in clinical care. Therapeutically, sodium–glucose cotransporter-2 (SGLT2) inhibitors represent the first pharmacologic agents to consistently reduce hospitalization and improve outcomes in HFpEF, while lifestyle modification, rehabilitation, and device-based interventions offer complementary benefits. Emerging strategies emphasize precision medicine, digital health, and biomarker-driven stratification.
Conclusion: HFpEF remains a major unexplained challenge in cardiovascular management. The efficacy of sodium–glucose cotransporter-2 inhibitors can mark a paradigm shift; however, significant weaknesses persist in diagnostic and therapeutic areas. Further progress depends on phenotype-specific, multimodal, and patient-centered strategies that combine clinical care, digital innovation, and molecular research.
2. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2020;17(9):559-73.
3. Budde H, Hassoun R, Mügge A, Kovács Á, Hamdani N. Current Understanding of Molecular Pathophysiology of Heart Failure with Preserved Ejection Fraction. Front Physiol. 2022;13:928232.
4. Cifuentes M, Verdejo HE, Castro PF, Corvalan AH, Ferreccio C, Quest AFG, et al. Low-Grade Chronic Inflammation: A Shared Mechanism for Chronic Diseases. Physiology (Bethesda). 2025;40(1):4-25.
5. Coppi F, Pagnoni G, Grossule F, Nassar A, Maini A, Masaracchia G, et al. Gender-Specific Differences in Diastolic Dysfunction and HFpEF: Pathophysiology, Diagnosis, and Therapeutic Strategies. J Cardiovasc Dev Dis. 2025;12(6):213.
6. D’Amario D, Migliaro S, Borovac JA, Restivo A, Vergallo R, Galli M, et al. Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction. Front Physiol. 2019;10:1347.
7. Formiga F, Nuñez J, Castillo J, Marcos MC, Egocheaga MI, García-Prieto CF, et al. Diagnosis of heart failure with preserved ejection fraction: a systematic narrative review of the evidence. Heart Fail Rev. 2024;29(1):179-89.
8. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020;22(8):1342-56.
9. Hamo CE, DeJong C, Hartshorne-Evans N, Lund LH, Shah SJ, Solomon SD, et al. Heart failure with preserved ejection fraction. Nat Rev Dis Primers. 2024;10(1):6.
10. Hutchings E, Loomes M, Butow P, Boyle FM. A systematic literature review of attitudes towards secondary use and sharing of health administrative and clinical trial data: a focus on consent. Syst Rev. 2021;10(1):132.
11. Ilonze OJ, Mazimba S. Racial and Ethnic Disparities in Heart Failure with Preserved Ejection Fraction: Epidemiology, Diagnosis, Management, and Outcomes. Curr Cardiovasc Risk Rep. 2024;19(1):1.
12. Jafleh EA, Alnaqbi FA, Almaeeni HA, Faqeeh S, Alzaabi MA, Al Zaman K. The Role of Wearable Devices in Chronic Disease Monitoring and Patient Care: A Comprehensive Review. Cureus. 2024;16(9):e68921.
13. Wilding JPH, Evans M, Fernando K, Gorriz JL, Cebrian A, Diggle J, et al. The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review. Diabetes Ther. 2022;13(5):847-72.
14. Stoicescu L, Crişan D, Morgovan C, Avram L, Ghibu S. Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach. Int J Mol Sci. 2024;25(2):794.
15. Czupryniak L, Mosenzon O, Rychlík I, Clodi M, Ebrahimi F, Janez A, et al. Barriers to early diagnosis of chronic kidney disease and use of sodium-glucose cotransporter-2 inhibitors for renal protection: A comprehensive review and call to action. Diabetes Obes Metab. 2024;26(10):4165-77.
16. Licordari R, Correale M, Bonanno S, Beltrami M, Ciccarelli M, Micari A, et al. Beyond Natriuretic Peptides: Unveiling the Power of Emerging Biomarkers in Heart Failure. Biomolecules. 2024;14(3):309.
17. Liew D, Audehm RG, Haikerwal D, Piazza P, Neville AM, Lim K, et al. Epidemiology of heart failure: Study of Heart failure in the Australian Primary carE setting (SHAPE). ESC Heart Fail. 2020;7(6):3871-80.
18. Murphy SP, Ibrahim NE, Januzzi JL. Heart Failure with Reduced Ejection Fraction. JAMA. 2020;324(5): 488-504.
19. Savji N, Meijers WC, Bartz TM, Bhambhani V, Cushman M, Nayor M, et al. The Association of Obesity and Cardiometabolic Traits with Incident HFpEF and HFrEF. JACC Heart Fail. 2018;6(8):701-9.
20. Packer M, Butler J, Zannad F, Filippatos G, Ferreira JP, Pocock SJ, et al. Effect of Empagliflozin on Worsening Heart Failure Events in Patients with Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial. Circulation. 2021;144(16):1284-94.
21. Padro T, Manfrini O, Bugiardini R, Canty J, Cenko E, De Luca G, et al. ESC Working Group on Coronary Pathophysiology and Microcirculation position paper on "coronary microvascular dysfunction in cardiovascular disease." Cardiovasc Res. 2020;116(4):741-55.
22. Po HW, Chu YC, Tsai HC, Lin CL, Chen CY, Ma MHM. Efficacy of Remote Health Monitoring in Reducing Hospital Readmissions Among High-Risk Postdischarge Patients: Prospective Cohort Study. JMIR Form Res. 2024;8:e53455.
23. Ramirez MF, Lau ES, Parekh JK, Pan AS, Owunna N, Wang D, et al. Obesity-Related Biomarkers Are Associated with Exercise Intolerance and HFpEF. Circ Heart Fail. 2023;16(11):e010618.
24. Reddy YNV, Borlaug BA, Gersh BJ. Management of Atrial Fibrillation Across the Spectrum of Heart Failure with Preserved and Reduced Ejection Fraction. Circulation. 2022;146(4):339-57.
25. Rist A, Sevre K, Wachtell K, Devereux RB, Aurigemma GP, Smiseth OA, et al. The current best drug treatment for hypertensive heart failure with preserved ejection fraction. Eur J Intern Med. 2024;120:3-10.
26. Roger VL. Epidemiology of Heart Failure. Circ Res. 2021;128(10):1421-34.
27. Roh J, Hill JA, Singh A, Valero-Muñoz M, Sam F. Heart Failure with Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models. Circ Res. 2022;130(12):1906-25.
28. Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023;118(17):3272-87.
29. Serenelli M, Jackson A, Dewan P, Jhund PS, Petrie MC, Rossignol P, et al. Mineralocorticoid Receptor Antagonists, Blood Pressure, and Outcomes in Heart Failure with Reduced Ejection Fraction. JACC Heart Fail. 2020;8(3):188-98.
30. Shah SJ, Borlaug BA, Kitzman DW, McCulloch AD, Blaxall BC, Agarwal R, et al. Research Priorities for Heart Failure with Preserved Ejection Fraction. Circulation. 2020;141(12):1001-26.
31. Shah SJ, Feldman T, Ricciardi MJ, Kahwash R, Lilly S, Litwin S, et al. One-Year Safety and Clinical Outcomes of a Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure with Preserved Ejection Fraction in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF I) Trial: A Randomized Clinical Trial. JAMA Cardiol. 2018;3(10):968-77.
32. Simmonds SJ, Cuijpers I, Heymans S, Jones EAV. Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding. Cells. 2020;9(1):242.
33. Søgaard MB, Andresen K, Kristiansen M. Systematic review of patient-engagement interventions: potentials for enhancing person-centred care for older patients with multimorbidity. BMJ Open. 2021;11(12):e048558.
34. Stolfo D, Uijl A, Vedin O, Strömberg A, Faxén UL, Rosano GMC, et al. Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum. JACC Heart Fail. 2019;7(6):505-15.
35. Talha KM, Pandey A, Fudim M, Butler J, Anker SD, Khan MS. Frailty and heart failure: State-of-the-art review. J Cachexia Sarcopenia Muscle. 2023;14(5):1959-72.
36. Tran TN, Le PH, Yang S, Luong T, Kim J. Rewiring the scar: translational advances in cardiac fibrosis. Korean J Physiol Pharmacol. 2025; 29(6):669-82.
37. Williams DM, Evans M. Dapagliflozin for Heart Failure with Preserved Ejection Fraction: Will the DELIVER Study Deliver? Diabetes Ther. 2020;11(10):2207-19.
38. Wintrich J, Kindermann I, Ukena C, Selejan S, Werner C, Maack C, et al. Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future. Clin Res Cardiol. 2020;109(9):1079-98.
39. Xu X, Li J, Zhu Z, Zhao L, Wang H, Song C, et al. A Comprehensive Review on Synergy of Multi-Modal Data and AI Technologies in Medical Diagnosis. Bioengineering (Basel). 2024;11(3):219.
40. Yamamoto K, Rakugi H. Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment. Hypertens Res. 2021;44(10):1239-50.
| Files | ||
| Issue | Vol 21 No 1 (2026) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jthc.v21i1.21285 | |
| Keywords | ||
| Heart Failure with Preserved Ejection Fraction Sodium-Glucose Transporter 2 Inhibitors Precision Medicine Artificial Intelligence Diagnostic Imaging Cardiovascular Diseases | ||
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