Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF
Heart failure with preserved ejection fraction (HFpEF) is a major public health challenge, affecting millions worldwide and placing a significant burden on healthcare systems due to high hospitalization rates and limited treatment options. HFpEF is characterized by impaired cardiac relaxation, or di...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2024.1512550/full |
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| author | Katherine L. Dominic Alexandra V. Schmidt Henk Granzier Kenneth S. Campbell Kenneth S. Campbell Julian E. Stelzer |
| author_facet | Katherine L. Dominic Alexandra V. Schmidt Henk Granzier Kenneth S. Campbell Kenneth S. Campbell Julian E. Stelzer |
| author_sort | Katherine L. Dominic |
| collection | DOAJ |
| description | Heart failure with preserved ejection fraction (HFpEF) is a major public health challenge, affecting millions worldwide and placing a significant burden on healthcare systems due to high hospitalization rates and limited treatment options. HFpEF is characterized by impaired cardiac relaxation, or diastolic dysfunction. However, there are no therapies that directly treat the primary feature of the disease. This is due in part to the complexity of normal diastolic function, and the challenge of isolating the mechanisms responsible for dysfunction in HFpEF. Without a clear understanding of the mechanisms driving diastolic dysfunction, progress in treatment development has been slow. In this review, we highlight three key areas of molecular dysregulation directly underlying impaired cardiac relaxation in HFpEF: altered calcium sensitivity in the troponin complex, impaired phosphorylation of myosin-binding protein C (cMyBP-C), and reduced titin compliance. We explore how targeting these pathways can restore normal relaxation, improve diastolic function, and potentially provide new therapeutic strategies for HFpEF treatment. Developing effective HFpEF therapies requires precision targeting to balance systolic and diastolic function, avoiding both upstream non-specificity and downstream rigidity. This review highlights three rational molecular targets with a strong mechanistic basis and potential for therapeutic success. |
| format | Article |
| id | doaj-art-bc48eeacf92a488ba39f62c1b920bc0f |
| institution | OA Journals |
| issn | 1664-042X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj-art-bc48eeacf92a488ba39f62c1b920bc0f2025-08-20T01:59:09ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2024-12-011510.3389/fphys.2024.15125501512550Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEFKatherine L. Dominic0Alexandra V. Schmidt1Henk Granzier2Kenneth S. Campbell3Kenneth S. Campbell4Julian E. Stelzer5Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United StatesDivision of Cardiovascular Medicine, University of Kentucky, Lexington, KY, United StatesDepartment of Physiology, University of Kentucky, Lexington, KY, United StatesDepartment of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesHeart failure with preserved ejection fraction (HFpEF) is a major public health challenge, affecting millions worldwide and placing a significant burden on healthcare systems due to high hospitalization rates and limited treatment options. HFpEF is characterized by impaired cardiac relaxation, or diastolic dysfunction. However, there are no therapies that directly treat the primary feature of the disease. This is due in part to the complexity of normal diastolic function, and the challenge of isolating the mechanisms responsible for dysfunction in HFpEF. Without a clear understanding of the mechanisms driving diastolic dysfunction, progress in treatment development has been slow. In this review, we highlight three key areas of molecular dysregulation directly underlying impaired cardiac relaxation in HFpEF: altered calcium sensitivity in the troponin complex, impaired phosphorylation of myosin-binding protein C (cMyBP-C), and reduced titin compliance. We explore how targeting these pathways can restore normal relaxation, improve diastolic function, and potentially provide new therapeutic strategies for HFpEF treatment. Developing effective HFpEF therapies requires precision targeting to balance systolic and diastolic function, avoiding both upstream non-specificity and downstream rigidity. This review highlights three rational molecular targets with a strong mechanistic basis and potential for therapeutic success.https://www.frontiersin.org/articles/10.3389/fphys.2024.1512550/fullHFpEFheart failure with preserved ejection fractioncMyBP-CcTnIcardiac troponin Ititin |
| spellingShingle | Katherine L. Dominic Alexandra V. Schmidt Henk Granzier Kenneth S. Campbell Kenneth S. Campbell Julian E. Stelzer Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF Frontiers in Physiology HFpEF heart failure with preserved ejection fraction cMyBP-C cTnI cardiac troponin I titin |
| title | Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF |
| title_full | Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF |
| title_fullStr | Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF |
| title_full_unstemmed | Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF |
| title_short | Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF |
| title_sort | mechanism based myofilament manipulation to treat diastolic dysfunction in hfpef |
| topic | HFpEF heart failure with preserved ejection fraction cMyBP-C cTnI cardiac troponin I titin |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2024.1512550/full |
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