Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged Mice
Background Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific ther...
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Wiley
2024-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.032641 |
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| author | Isabel N. Schellinger Angelika Dannert Annet Hoffmann Giriprakash Chodisetti Karin Mattern Anne Petzold Nora Klöting Andreas Schuster Markus U. Wagenhäuser Fabian Emrich Michael Stumvoll Gerd Hasenfuß Uwe Raaz |
| author_facet | Isabel N. Schellinger Angelika Dannert Annet Hoffmann Giriprakash Chodisetti Karin Mattern Anne Petzold Nora Klöting Andreas Schuster Markus U. Wagenhäuser Fabian Emrich Michael Stumvoll Gerd Hasenfuß Uwe Raaz |
| author_sort | Isabel N. Schellinger |
| collection | DOAJ |
| description | Background Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age‐related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age‐related arterial fibrotic remodeling and stiffening in 1‐year‐old mice. Methods and Results Treatment of in 1‐year‐old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse‐wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. Conclusions This study provides preclinical mechanistic evidence indicating that ARNI‐based interventions may counteract age‐related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly. |
| format | Article |
| id | doaj-art-3d2e57d5b5eb4b28953b6defcea1c7de |
| institution | OA Journals |
| issn | 2047-9980 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-3d2e57d5b5eb4b28953b6defcea1c7de2025-08-20T02:26:40ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802024-02-0113410.1161/JAHA.123.032641Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged MiceIsabel N. Schellinger0Angelika Dannert1Annet Hoffmann2Giriprakash Chodisetti3Karin Mattern4Anne Petzold5Nora Klöting6Andreas Schuster7Markus U. Wagenhäuser8Fabian Emrich9Michael Stumvoll10Gerd Hasenfuß11Uwe Raaz12Department of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyDepartment of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyDepartment for Endocrinology, Nephrology and Rheumatology University Medical Center Leipzig, University of Leipzig Leipzig GermanyDepartment of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyDepartment of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyDepartment of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyDepartment for Endocrinology, Nephrology and Rheumatology University Medical Center Leipzig, University of Leipzig Leipzig GermanyDepartment of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyDepartment of Vascular and Endovascular Surgery University Hospital Düsseldorf, Heinrich‐Heine‐University Düsseldorf GermanyDepartment of Cardiothoracic and Vascular Surgery Goethe University Hospital Frankfurt Frankfurt GermanyDepartment for Endocrinology, Nephrology and Rheumatology University Medical Center Leipzig, University of Leipzig Leipzig GermanyDepartment of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyDepartment of Cardiology and Pneumology Heart Center at the University Medical Center Göttingen Göttingen GermanyBackground Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age‐related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age‐related arterial fibrotic remodeling and stiffening in 1‐year‐old mice. Methods and Results Treatment of in 1‐year‐old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse‐wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. Conclusions This study provides preclinical mechanistic evidence indicating that ARNI‐based interventions may counteract age‐related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly.https://www.ahajournals.org/doi/10.1161/JAHA.123.032641agingangiotensin receptor antagonistsfibrosismiceneprilysinpulse wave analysis |
| spellingShingle | Isabel N. Schellinger Angelika Dannert Annet Hoffmann Giriprakash Chodisetti Karin Mattern Anne Petzold Nora Klöting Andreas Schuster Markus U. Wagenhäuser Fabian Emrich Michael Stumvoll Gerd Hasenfuß Uwe Raaz Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged Mice Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease aging angiotensin receptor antagonists fibrosis mice neprilysin pulse wave analysis |
| title | Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged Mice |
| title_full | Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged Mice |
| title_fullStr | Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged Mice |
| title_full_unstemmed | Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged Mice |
| title_short | Angiotensin Receptor–Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle‐Aged Mice |
| title_sort | angiotensin receptor neprilysin inhibition sacubitril valsartan reduces structural arterial stiffness in middle aged mice |
| topic | aging angiotensin receptor antagonists fibrosis mice neprilysin pulse wave analysis |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.032641 |
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