Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor Expression
Background The pathways of diastolic dysfunction and heart failure with preserved ejection fraction driven by lipotoxicity with metabolic syndrome are incompletely understood. Thus, there is an urgent need for animal models that accurately mimic the metabolic and cardiovascular phenotypes of this ph...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-09-01
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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.122.027216 |
| _version_ | 1827746389717680128 |
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| author | Monique Williams Jose Manuel Condor Capcha Camila Iansen Irion Grace Seo Guerline Lambert Ali Kamiar Keyvan Yousefi Rosemeire Kanashiro‐Takeuchi Lauro Takeuchi Ali G. Saad Armando Mendez Keith A. Webster Jeffrey J. Goldberger Joshua M. Hare Lina A. Shehadeh |
| author_facet | Monique Williams Jose Manuel Condor Capcha Camila Iansen Irion Grace Seo Guerline Lambert Ali Kamiar Keyvan Yousefi Rosemeire Kanashiro‐Takeuchi Lauro Takeuchi Ali G. Saad Armando Mendez Keith A. Webster Jeffrey J. Goldberger Joshua M. Hare Lina A. Shehadeh |
| author_sort | Monique Williams |
| collection | DOAJ |
| description | Background The pathways of diastolic dysfunction and heart failure with preserved ejection fraction driven by lipotoxicity with metabolic syndrome are incompletely understood. Thus, there is an urgent need for animal models that accurately mimic the metabolic and cardiovascular phenotypes of this phenogroup for mechanistic studies. Methods and Results Hyperlipidemia was induced in WT‐129 mice by 4 weeks of biweekly poloxamer‐407 intraperitoneal injections with or without a single intravenous injection of adeno‐associatedvirus 9–cardiac troponin T–low‐density lipoprotein receptor (n=31), or single intravenous injection with adeno‐associatedvirus 9–cardiac troponin T–low‐density lipoprotein receptor alone (n=10). Treatment groups were compared with untreated or placebo controls (n=37). Echocardiography, blood pressure, whole‐body plethysmography, ECG telemetry, activity wheel monitoring, and biochemical and histological changes were assessed at 4 to 8 weeks. At 4 weeks, double treatment conferred diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Blood pressure and whole‐body plethysmography results were normal, but respiration decreased at 8 weeks (P<0.01). ECG and activity wheel monitoring, respectively, indicated heart block and decreased exercise activity (P<0.001). Double treatment promoted elevated myocardial lipids including total cholesterol, fibrosis, increased wet/dry lung (P<0.001) and heart weight/body weight (P<0.05). Xanthelasma, ascites, and cardiac ischemia were evident in double and single (p407) groups. Sudden death occurred between 6 and 12 weeks in double and single (p407) treatment groups. Conclusions We present a novel model of heart failure with preserved ejection fraction driven by dyslipidemia where mice acquire diastolic dysfunction, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved ejection fraction in the absence of obesity, hypertension, kidney disease, or diabetes. The model can be applied to dissect pathways of metabolic syndrome that drive diastolic dysfunction in this lipotoxicity‐mediated heart failure with preserved ejection fraction phenogroup mimic. |
| first_indexed | 2024-03-11T05:23:42Z |
| format | Article |
| id | doaj.art-432212ebf6704b49a53ed9538b43891e |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-11T05:23:42Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-432212ebf6704b49a53ed9538b43891e2023-11-17T17:38:24ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-09-01111710.1161/JAHA.122.027216Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor ExpressionMonique Williams0Jose Manuel Condor Capcha1Camila Iansen Irion2Grace Seo3Guerline Lambert4Ali Kamiar5Keyvan Yousefi6Rosemeire Kanashiro‐Takeuchi7Lauro Takeuchi8Ali G. Saad9Armando Mendez10Keith A. Webster11Jeffrey J. Goldberger12Joshua M. Hare13Lina A. Shehadeh14Department of Medicine Division of Cardiology University of Miami Leonard M. Miller School of Medicine Miami FLDepartment of Medicine Division of Cardiology University of Miami Leonard M. Miller School of Medicine Miami FLDepartment of Medicine Division of Cardiology University of Miami Leonard M. Miller School of Medicine Miami FLDepartment of Medical Education University of Miami Leonard M. Miller School of Medicine Miami FLDepartment of Medicine Division of Cardiology University of Miami Leonard M. Miller School of Medicine Miami FLInterdisciplinary Stem Cell Institute University of Miami Leonard M. Miller School of Medicine Miami FLInterdisciplinary Stem Cell Institute University of Miami Leonard M. Miller School of Medicine Miami FLInterdisciplinary Stem Cell Institute University of Miami Leonard M. Miller School of Medicine Miami FLInterdisciplinary Stem Cell Institute University of Miami Leonard M. Miller School of Medicine Miami FLDepartments of Pathology and Pediatrics University of Miami Leonard M. Miller School of Medicine Miami FLDivision of Endocrinology, Diabetes and Metabolism Diabetes Research Institute University of Miami Leonard M. Miller School of Medicine Miami FLCullen Eye Institute Baylor College of Medicine Houston TXDepartment of Medicine Division of Cardiology University of Miami Leonard M. Miller School of Medicine Miami FLInterdisciplinary Stem Cell Institute University of Miami Leonard M. Miller School of Medicine Miami FLDepartment of Medicine Division of Cardiology University of Miami Leonard M. Miller School of Medicine Miami FLBackground The pathways of diastolic dysfunction and heart failure with preserved ejection fraction driven by lipotoxicity with metabolic syndrome are incompletely understood. Thus, there is an urgent need for animal models that accurately mimic the metabolic and cardiovascular phenotypes of this phenogroup for mechanistic studies. Methods and Results Hyperlipidemia was induced in WT‐129 mice by 4 weeks of biweekly poloxamer‐407 intraperitoneal injections with or without a single intravenous injection of adeno‐associatedvirus 9–cardiac troponin T–low‐density lipoprotein receptor (n=31), or single intravenous injection with adeno‐associatedvirus 9–cardiac troponin T–low‐density lipoprotein receptor alone (n=10). Treatment groups were compared with untreated or placebo controls (n=37). Echocardiography, blood pressure, whole‐body plethysmography, ECG telemetry, activity wheel monitoring, and biochemical and histological changes were assessed at 4 to 8 weeks. At 4 weeks, double treatment conferred diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Blood pressure and whole‐body plethysmography results were normal, but respiration decreased at 8 weeks (P<0.01). ECG and activity wheel monitoring, respectively, indicated heart block and decreased exercise activity (P<0.001). Double treatment promoted elevated myocardial lipids including total cholesterol, fibrosis, increased wet/dry lung (P<0.001) and heart weight/body weight (P<0.05). Xanthelasma, ascites, and cardiac ischemia were evident in double and single (p407) groups. Sudden death occurred between 6 and 12 weeks in double and single (p407) treatment groups. Conclusions We present a novel model of heart failure with preserved ejection fraction driven by dyslipidemia where mice acquire diastolic dysfunction, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved ejection fraction in the absence of obesity, hypertension, kidney disease, or diabetes. The model can be applied to dissect pathways of metabolic syndrome that drive diastolic dysfunction in this lipotoxicity‐mediated heart failure with preserved ejection fraction phenogroup mimic.https://www.ahajournals.org/doi/10.1161/JAHA.122.027216heart failurehyperlipidemiasmicestroke volume |
| spellingShingle | Monique Williams Jose Manuel Condor Capcha Camila Iansen Irion Grace Seo Guerline Lambert Ali Kamiar Keyvan Yousefi Rosemeire Kanashiro‐Takeuchi Lauro Takeuchi Ali G. Saad Armando Mendez Keith A. Webster Jeffrey J. Goldberger Joshua M. Hare Lina A. Shehadeh Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor Expression Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease heart failure hyperlipidemias mice stroke volume |
| title | Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor Expression |
| title_full | Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor Expression |
| title_fullStr | Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor Expression |
| title_full_unstemmed | Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor Expression |
| title_short | Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low‐Density Lipoprotein Receptor Expression |
| title_sort | mouse model of heart failure with preserved ejection fraction driven by hyperlipidemia and enhanced cardiac low density lipoprotein receptor expression |
| topic | heart failure hyperlipidemias mice stroke volume |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.027216 |
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