{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:24:41Z","timestamp":1792679081436,"version":"4.5.0"},"reference-count":83,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge, accounting for more than half of all cases of heart failure, for which there are currently no effective treatments. Emerging evidence identifies mitochondrial dysfunction as a central mechanism linking metabolic comorbidities, systemic inflammation, and energy failure in HFpEF. This review provides a comprehensive overview of the metabolic\u2013mitochondrial mechanisms underlying the pathophysiology of HFpEF. Loss of metabolic flexibility, characterized by reduced fatty acid and glucose oxidation, leads to energy inefficiency, lipid accumulation, and oxidative stress. Structural and functional mitochondrial abnormalities, including damaged cristae, altered fission-fusion dynamics, and impaired oxidative phosphorylation, contribute to diastolic dysfunction and ventricular remodeling. In parallel, chronic inflammation and redox imbalance amplify mitochondrial damage through cytokine- and ROS-mediated pathways, creating a cycle of bioenergetic failure. From a therapeutic perspective, strategies aimed at restoring mitochondrial homeostasis, such as physical training, metabolic modulation, SGLT2 inhibition, ketone supplementation, and mitochondria-targeted antioxidants, show promising preclinical results. However, clinical translation remains limited. Deepening the understanding of mitochondrial metabolism could enable the development of personalized treatments capable of improving outcomes for HFpEF patients.<\/jats:p>","DOI":"10.3390\/ijms27010284","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T05:28:19Z","timestamp":1766986099000},"page":"284","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pathophysiology of HFpEF: Insights from a Metabolic\u2013Mitochondrial Perspective"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1658-8470","authenticated-orcid":false,"given":"Cristina","family":"Gatto","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, University of Salerno \u201cScuola Medica Salernitana\u201d, 84081 Baronissi, Italy"},{"name":"Scuola di Specializzazione in Patologia Clinica e Biochimica Clinica, University of Salerno \u201cScuola Medica Salernitana\u201d, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Rusciano","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, University of Salerno \u201cScuola Medica Salernitana\u201d, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2197-5355","authenticated-orcid":false,"given":"Valeria","family":"Visco","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, University of Salerno \u201cScuola Medica Salernitana\u201d, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Vecchione","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, University of Salerno \u201cScuola Medica Salernitana\u201d, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-1960","authenticated-orcid":false,"given":"Michele","family":"Ciccarelli","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, University of Salerno \u201cScuola Medica Salernitana\u201d, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1093\/cvr\/cvac013","article-title":"Global burden of heart failure: A comprehensive and updated review of epidemiology","volume":"118","author":"Savarese","year":"2023","journal-title":"Cardiovasc. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e007034","DOI":"10.1161\/CIRCHEARTFAILURE.120.007034","article-title":"Efficacy and Safety of Sacubitril\/Valsartan in High-Risk Patients in the PIONEER-HF Trial","volume":"14","author":"Berg","year":"2021","journal-title":"Circ. Heart Fail."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.tcm.2018.01.001","article-title":"Heart failure with preserved ejection fraction: Classification based upon phenotype is essential for diagnosis and treatment","volume":"28","author":"Xanthopoulos","year":"2018","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Stoicescu, L., Crisan, D., Morgovan, C., Avram, L., and Ghibu, S. (2024). Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25020794"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev-med-042220-022745","article-title":"Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies","volume":"73","author":"Omote","year":"2022","journal-title":"Annu. Rev. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrcardio.2017.65","article-title":"Epidemiology of heart failure with preserved ejection fraction","volume":"14","author":"Dunlay","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1093\/eurheartj\/ehm037","article-title":"How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology","volume":"28","author":"Paulus","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41569-020-0363-2","article-title":"Evaluation and management of heart failure with preserved ejection fraction","volume":"17","author":"Borlaug","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1093\/eurjhf\/hfq121","article-title":"Epidemiology and clinical course of heart failure with preserved ejection fraction","volume":"13","author":"Lam","year":"2011","journal-title":"Eur. J. Heart Fail."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jacc.2013.02.092","article-title":"A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation","volume":"62","author":"Paulus","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1136\/heartjnl-2015-307787","article-title":"From comorbidities to heart failure with preserved ejection fraction: A story of oxidative stress","volume":"102","author":"Franssen","year":"2016","journal-title":"Heart"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Weerts, J., Mourmans, S.G.J., Barandiaran Aizpurua, A., Schroen, B.L.M., Knackstedt, C., Eringa, E., Houben, A., and van Empel, V.P.M. (2022). The Role of Systemic Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction. Biomolecules, 12.","DOI":"10.3390\/biom12020278"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0355-7","article-title":"Mitochondrial dysfunction and oxidative stress in heart disease","volume":"51","author":"Peoples","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s10741-024-10479-7","article-title":"Focusing on microvascular function in heart failure with preserved ejection fraction","volume":"30","author":"Velollari","year":"2025","journal-title":"Heart Fail. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102461","DOI":"10.1016\/j.coph.2024.102461","article-title":"In the heart and beyond: Mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF)","volume":"76","author":"Bhattarai","year":"2024","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"166208","DOI":"10.1016\/j.bbadis.2021.166208","article-title":"Mitochondrial function, dynamics and quality control in the pathophysiology of HFpEF","volume":"1867","author":"Perez","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1161\/CIRCULATIONAHA.118.036259","article-title":"Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction","volume":"139","author":"Kumar","year":"2019","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1152\/physiol.00004.2023","article-title":"Inflammatory Mechanisms in Heart Failure with Preserved Ejection Fraction","volume":"38","author":"Daou","year":"2023","journal-title":"Physiology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9","DOI":"10.20517\/jca.2022.42","article-title":"The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure","volume":"3","author":"Werbner","year":"2023","journal-title":"J. Cardiovasc. Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s00109-015-1254-6","article-title":"Mitophagy and heart failure","volume":"93","author":"Shires","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"H2080","DOI":"10.1152\/ajpheart.00917.2020","article-title":"Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases","volume":"320","author":"Kirkman","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Liu, M., Lv, J., Pan, Z., Wang, D., Zhao, L., and Guo, X. (2022). Mitochondrial dysfunction in heart failure and its therapeutic implications. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.945142"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1161\/CIRCRESAHA.121.318241","article-title":"Cardiac Energy Metabolism in Heart Failure","volume":"128","author":"Lopaschuk","year":"2021","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Karwi, Q.G., Uddin, G.M., Ho, K.L., and Lopaschuk, G.D. (2018). Loss of Metabolic Flexibility in the Failing Heart. Front. Cardiovasc. Med., 5.","DOI":"10.3389\/fcvm.2018.00068"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1161\/CIRCRESAHA.113.300376","article-title":"Cardiac metabolism in heart failure: Implications beyond ATP production","volume":"113","author":"Doenst","year":"2013","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"158","DOI":"10.2174\/1874192401610010158","article-title":"Impaired Myocardial Bioenergetics in HFpEF and the Role of Antioxidants","volume":"10","author":"Hiebert","year":"2016","journal-title":"Open Cardiovasc. Med. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Paraskevaidis, I., Tsougos, E., and Kourek, C. (2025). One Syndrome, Many Faces: A Unified Perspective on Heart Failure Phenotypes. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26188960"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/ejhf.1617","article-title":"Myocardial adipose deposition and the development of heart failure with preserved ejection fraction","volume":"22","author":"Wu","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1172\/JCI10947","article-title":"A novel mouse model of lipotoxic cardiomyopathy","volume":"107","author":"Chiu","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H1267","DOI":"10.1152\/ajpheart.00121.2025","article-title":"Cardiac energy substrate utilization in heart failure with preserved ejection fraction: Reconciling conflicting evidence on fatty acid and glucose metabolism","volume":"328","author":"Shehadeh","year":"2025","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1093\/cvr\/cvae006","article-title":"Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction","volume":"120","author":"Sun","year":"2024","journal-title":"Cardiovasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1161\/CIRCRESAHA.120.317046","article-title":"NAD+ Repletion Reverses Heart Failure With Preserved Ejection Fraction","volume":"128","author":"Tong","year":"2021","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/ehf2.12176","article-title":"Associations between acylcarnitine to free carnitine ratio and adverse prognosis in heart failure patients with reduced or preserved ejection fraction","volume":"4","author":"Yoshihisa","year":"2017","journal-title":"ESC Heart Fail."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1161\/CIRCHEARTFAILURE.112.966705","article-title":"Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: A metabolic contribution to heart failure with normal ejection fraction","volume":"5","author":"Mori","year":"2012","journal-title":"Circ. Heart Fail."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e70319","DOI":"10.1002\/mco2.70319","article-title":"Mitochondrial Quality Control in Health and Disease","volume":"6","author":"Ye","year":"2025","journal-title":"MedComm"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s44161-024-00516-x","article-title":"Myocardial ultrastructure of human heart failure with preserved ejection fraction","volume":"3","author":"Meddeb","year":"2024","journal-title":"Nat. Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Uchikado, Y., Ikeda, Y., and Ohishi, M. (2022). Current Understanding of the Pivotal Role of Mitochondrial Dynamics in Cardiovascular Diseases and Senescence. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.905072"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Givvimani, S., Munjal, C., Tyagi, N., Sen, U., Metreveli, N., and Tyagi, S.C. (2012). Mitochondrial division\/mitophagy inhibitor (Mdivi) ameliorates pressure overload induced heart failure. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032388"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e038945","DOI":"10.1161\/JAHA.124.038945","article-title":"Myocardial Proteome in Human Heart Failure With Preserved Ejection Fraction","volume":"14","author":"Jani","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11389","DOI":"10.1073\/pnas.1513047112","article-title":"Mitochondrial calcium overload is a key determinant in heart failure","volume":"112","author":"Santulli","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1007\/s12265-025-10591-5","article-title":"Mitochondrial Dysfunction in HFpEF: Potential Interventions Through Exercise","volume":"18","author":"Cui","year":"2025","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e005131","DOI":"10.1161\/CIRCHEARTFAILURE.118.005131","article-title":"Mitochondrial Morphology, Dynamics, and Function in Human Pressure Overload or Ischemic Heart Disease With Preserved or Reduced Ejection Fraction","volume":"12","author":"Chaanine","year":"2019","journal-title":"Circ. Heart Fail."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/embor.2010.50","article-title":"The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms","volume":"11","author":"Landes","year":"2010","journal-title":"EMBO Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bode, D., Wen, Y., Hegemann, N., Primessnig, U., Parwani, A., Boldt, L.H., MPieske, B., RHeinzel, F., and Hohendanner, F. (2020). Oxidative Stress and Inflammatory Modulation of Ca2+ Handling in Metabolic HFpEF-Related Left Atrial Cardiomyopathy. Antioxidants, 9.","DOI":"10.3390\/antiox9090860"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zhang, W., Zhang, H., Yao, W., Li, L., Niu, P., Huo, Y., and Tan, W. (2020). Morphometric, Hemodynamic, and Multi-Omics Analyses in Heart Failure Rats with Preserved Ejection Fraction. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093362"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.jchf.2016.03.011","article-title":"Skeletal Muscle Mitochondrial Content, Oxidative Capacity, and Mfn2 Expression Are Reduced in Older Patients With Heart Failure and Preserved Ejection Fraction and Are Related to Exercise Intolerance","volume":"4","author":"Molina","year":"2016","journal-title":"JACC Heart Fail."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Martinez, C.S., Zheng, A., and Xiao, Q. (2024). Mitochondrial Reactive Oxygen Species Dysregulation in Heart Failure with Preserved Ejection Fraction: A Fraction of the Whole. Antioxidants, 13.","DOI":"10.20944\/preprints202409.2167.v1"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1093\/cvr\/cvy038","article-title":"Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening","volume":"114","author":"Sorop","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1002\/ehf2.13424","article-title":"Neutrophil-to-lymphocyte ratio and outcomes in patients with new-onset or worsening heart failure with reduced and preserved ejection fraction","volume":"8","author":"Curran","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s00059-002-2354-y","article-title":"Cardiac fibrosis as a cause of diastolic dysfunction","volume":"27","author":"Burlew","year":"2002","journal-title":"Herz"},{"key":"ref_51","first-page":"123","article-title":"The effect of L-carnitine on the energy metabolism of isolated rat heart perfused by Langendorff\u2019s method using 31P-NMR spectroscopy","volume":"31","author":"Loster","year":"1990","journal-title":"Z. Med. Lab. Diagn."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1007\/s12551-020-00742-0","article-title":"The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases","volume":"12","author":"Zhazykbayeva","year":"2020","journal-title":"Biophys. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1084\/jem.20171274","article-title":"Cardiac macrophages promote diastolic dysfunction","volume":"215","author":"Hulsmans","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1161\/01.RES.86.5.494","article-title":"NAD(P)H oxidase: Role in cardiovascular biology and disease","volume":"86","author":"Griendling","year":"2000","journal-title":"Circ. Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Gevaert, A.B., Boen, J.R.A., Segers, V.F., and Van Craenenbroeck, E.M. (2019). Heart Failure With Preserved Ejection Fraction: A Review of Cardiac and Noncardiac Pathophysiology. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00638"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1177\/0148607111434963","article-title":"Oxidative stress","volume":"36","author":"Preiser","year":"2012","journal-title":"J. Parenter. Enteral Nutr."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Mongirdiene, A., Skrodenis, L., Varoneckaite, L., Mierkyte, G., and Gerulis, J. (2022). Reactive Oxygen Species Induced Pathways in Heart Failure Pathogenesis and Potential Therapeutic Strategies. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030602"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4401","DOI":"10.1038\/s41598-020-61244-3","article-title":"Downregulation of respiratory complex I mediates major signalling changes triggered by TOR activation","volume":"10","author":"Magnin","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Pinzon-Fernandez, M.V., Saavedra-Torres, J.S., Lopez Garzon, N.A., Pachon-Bueno, J.S., Tamayo-Giraldo, F.J., Rojas Gomez, M.C., Arias-Intriago, M., Gaibor-Pazmino, A., Lopez-Cortes, A., and Izquierdo-Condoy, J.S. (2025). NLRP3 and beyond: Inflammasomes as central cellular hub and emerging therapeutic target in inflammation and disease. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1624770"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1161\/CIRCHEARTFAILURE.114.001615","article-title":"Exercise training in patients with heart failure and preserved ejection fraction: Meta-analysis of randomized control trials","volume":"8","author":"Pandey","year":"2015","journal-title":"Circ. Heart Fail."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1001\/jama.2015.17346","article-title":"Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial","volume":"315","author":"Kitzman","year":"2016","journal-title":"JAMA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1161\/CIRCHEARTFAILURE.113.000481","article-title":"Low-sodium DASH diet improves diastolic function and ventricular-arterial coupling in hypertensive heart failure with preserved ejection fraction","volume":"6","author":"Hummel","year":"2013","journal-title":"Circ. Heart Fail."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1161\/HYPERTENSIONAHA.119.14057","article-title":"Medical Therapies for Heart Failure With Preserved Ejection Fraction","volume":"75","author":"Kjeldsen","year":"2020","journal-title":"Hypertension"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1056\/NEJMoa2206286","article-title":"Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction","volume":"387","author":"Solomon","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in Heart Failure with a Preserved Ejection Fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_67","first-page":"641","article-title":"Ranolazine: A new approach to treating an old problem","volume":"37","author":"Reddy","year":"2010","journal-title":"Tex. Heart Inst. J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1080\/15548627.2017.1325062","article-title":"Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure","volume":"13","author":"Campos","year":"2017","journal-title":"Autophagy"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.freeradbiomed.2007.12.033","article-title":"Regulation of mitochondrial uncoupling respiration during exercise in rat heart: Role of reactive oxygen species (ROS) and uncoupling protein 2","volume":"44","author":"Bo","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"113471","DOI":"10.1016\/j.isci.2025.113471","article-title":"Unlocking metabolic flexibility in heart failure with preserved ejection fraction: Bridging fundamental mechanisms to clinical innovation","volume":"28","author":"Xia","year":"2025","journal-title":"iScience"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1161\/CIRCRESAHA.120.317933","article-title":"Targeting Mitochondria-Inflammation Circuit by beta-Hydroxybutyrate Mitigates HFpEF","volume":"128","author":"Deng","year":"2021","journal-title":"Circ. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1161\/CIRCULATIONAHA.124.069732","article-title":"Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction","volume":"150","author":"Gopalasingam","year":"2024","journal-title":"Circulation"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1186\/s12933-025-02767-9","article-title":"The effects of SGLT2i on cardiac metabolism in patients with HFpEF: Fact or fiction?","volume":"24","author":"Cinti","year":"2025","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1093\/cvr\/cvaa123","article-title":"Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Galpha oxidation","volume":"117","author":"Kolijn","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1111\/dom.13814","article-title":"Sodium-glucose co-transporter inhibitors: Medications that mimic fasting for cardiovascular prevention","volume":"21","author":"Giaccari","year":"2019","journal-title":"Diabetes Obes. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e040093","DOI":"10.1161\/JAHA.124.040093","article-title":"Sodium Glucose Transporter 2 Inhibitor Protects Against Heart Failure With Preserved Ejection Fraction: Preclinical \u201c2-Hit\u201d Model Reveals Autophagy Enhancement Via AMP-Activated Protein Kinase\/Mammalian Target of Rapamycin Complex 1 Pathway","volume":"14","author":"Hu","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12933-020-01208-z","article-title":"Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF","volume":"20","author":"Bode","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s10103-023-03801-6","article-title":"Photobiomodulation at molecular, cellular, and systemic levels","volume":"38","author":"Ribeiro","year":"2023","journal-title":"Lasers Med. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3934\/biophy.2017.3.337","article-title":"Mechanisms and applications of the anti-inflammatory effects of photobiomodulation","volume":"4","author":"Hamblin","year":"2017","journal-title":"AIMS Biophys."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Dashdorj, A., Jyothi, K.R., Lim, S., Jo, A., Nguyen, M.N., Ha, J., Yoon, K.S., Kim, H.J., Park, J.H., and Murphy, M.P. (2013). Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines. BMC Med., 11.","DOI":"10.1186\/1741-7015-11-178"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"101100","DOI":"10.1016\/j.redox.2019.101100","article-title":"Mitoquinone ameliorates pressure overload-induced cardiac fibrosis and left ventricular dysfunction in mice","volume":"21","author":"Goh","year":"2019","journal-title":"Redox Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1161\/HYPERTENSIONAHA.117.10787","article-title":"Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults","volume":"71","author":"Rossman","year":"2018","journal-title":"Hypertension"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s11897-022-00550-5","article-title":"Harnessing NAD+ Metabolism as Therapy for Cardiometabolic Diseases","volume":"19","author":"Chakraborty","year":"2022","journal-title":"Curr. Heart Fail. 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