{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:38:18Z","timestamp":1792024698942,"version":"4.4.0"},"reference-count":393,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"British Heart Foundation","award":["PG\/15\/11\/31279"],"award-info":[{"award-number":["PG\/15\/11\/31279"]}]},{"name":"British Heart Foundation","award":["PG\/15\/86\/31723"],"award-info":[{"award-number":["PG\/15\/86\/31723"]}]},{"name":"British Heart Foundation","award":["PG\/20\/10458"],"award-info":[{"award-number":["PG\/20\/10458"]}]},{"name":"British Heart Foundation","award":["PG\/23\/11371"],"award-info":[{"award-number":["PG\/23\/11371"]}]},{"name":"National Institute for Health Research Biomedical Research Center at Barts","award":["PG\/15\/11\/31279"],"award-info":[{"award-number":["PG\/15\/11\/31279"]}]},{"name":"National Institute for Health Research Biomedical Research Center at Barts","award":["PG\/15\/86\/31723"],"award-info":[{"award-number":["PG\/15\/86\/31723"]}]},{"name":"National Institute for Health Research Biomedical Research Center at Barts","award":["PG\/20\/10458"],"award-info":[{"award-number":["PG\/20\/10458"]}]},{"name":"National Institute for Health Research Biomedical Research Center at Barts","award":["PG\/23\/11371"],"award-info":[{"award-number":["PG\/23\/11371"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) is a multifarious syndrome, accounting for over half of heart failure (HF) patients receiving clinical treatment. The prevalence of HFpEF is rapidly increasing in the coming decades as the global population ages. It is becoming clearer that HFpEF has a lot of different causes, which makes it challenging to find effective treatments. Currently, there are no proven treatments for people with deteriorating HF or HFpEF. Although the pathophysiologic foundations of HFpEF are complex, excessive reactive oxygen species (ROS) generation and increased oxidative stress caused by mitochondrial dysfunction seem to play a critical role in the pathogenesis of HFpEF. Emerging evidence from animal models and human myocardial tissues from failed hearts shows that mitochondrial aberrations cause a marked increase in mitochondrial ROS (mtROS) production and oxidative stress. Furthermore, studies have reported that common HF medications like beta blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists indirectly reduce the production of mtROS. Despite the harmful effects of ROS on cardiac remodeling, maintaining mitochondrial homeostasis and cardiac functions requires small amounts of ROS. In this review, we will provide an overview and discussion of the recent findings on mtROS production, its threshold for imbalance, and the subsequent dysfunction that leads to related cardiac and systemic phenotypes in the context of HFpEF. We will also focus on newly discovered cellular and molecular mechanisms underlying ROS dysregulation, current therapeutic options, and future perspectives for treating HFpEF by targeting mtROS and the associated signal molecules.<\/jats:p>","DOI":"10.3390\/antiox13111330","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T06:55:37Z","timestamp":1730357737000},"page":"1330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Mitochondrial Reactive Oxygen Species Dysregulation in Heart Failure with Preserved Ejection Fraction: A Fraction of the Whole"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5742-3635","authenticated-orcid":false,"given":"Caroline Silveira","family":"Martinez","sequence":"first","affiliation":[{"name":"Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ancheng","family":"Zheng","sequence":"additional","affiliation":[{"name":"Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9101-0498","authenticated-orcid":false,"given":"Qingzhong","family":"Xiao","sequence":"additional","affiliation":[{"name":"Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1093\/eurheartj\/ehab368","article-title":"2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"42","author":"McDonagh","year":"2021","journal-title":"Eur. 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