Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction
Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aime...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.122.027164 |
| _version_ | 1811170076237234176 |
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| author | Bence Hegyi Juliana Mira Hernandez Christopher Y. Ko Junyoung Hong Erin Y. Shen Emily R. Spencer Daria Smoliarchuk Manuel F. Navedo Donald M. Bers Julie Bossuyt |
| author_facet | Bence Hegyi Juliana Mira Hernandez Christopher Y. Ko Junyoung Hong Erin Y. Shen Emily R. Spencer Daria Smoliarchuk Manuel F. Navedo Donald M. Bers Julie Bossuyt |
| author_sort | Bence Hegyi |
| collection | DOAJ |
| description | Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor–deficient db/db mice with a 4‐week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium‐glucose cotransporter‐2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B‐type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short‐term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone‐treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology. |
| first_indexed | 2024-04-10T16:51:31Z |
| format | Article |
| id | doaj.art-f894cdcd88b24aaf9dd73caf14ff55d9 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-10T16:51:31Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-f894cdcd88b24aaf9dd73caf14ff55d92023-02-07T16:03:22ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-12-01112310.1161/JAHA.122.027164Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection FractionBence Hegyi0Juliana Mira Hernandez1Christopher Y. Ko2Junyoung Hong3Erin Y. Shen4Emily R. Spencer5Daria Smoliarchuk6Manuel F. Navedo7Donald M. Bers8Julie Bossuyt9Department of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CADepartment of Pharmacology University of California Davis CABackground The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor–deficient db/db mice with a 4‐week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium‐glucose cotransporter‐2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B‐type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short‐term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone‐treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.https://www.ahajournals.org/doi/10.1161/JAHA.122.027164arrhythmiadiabetesHFpEFmineralocorticoidSGLT2 inhibitor |
| spellingShingle | Bence Hegyi Juliana Mira Hernandez Christopher Y. Ko Junyoung Hong Erin Y. Shen Emily R. Spencer Daria Smoliarchuk Manuel F. Navedo Donald M. Bers Julie Bossuyt Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease arrhythmia diabetes HFpEF mineralocorticoid SGLT2 inhibitor |
| title | Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction |
| title_full | Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction |
| title_fullStr | Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction |
| title_full_unstemmed | Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction |
| title_short | Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction |
| title_sort | diabetes and excess aldosterone promote heart failure with preserved ejection fraction |
| topic | arrhythmia diabetes HFpEF mineralocorticoid SGLT2 inhibitor |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.027164 |
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