A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model
The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proli...
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MDPI AG
2020-11-01
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| Series: | Journal of Cardiovascular Development and Disease |
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| Online Access: | https://www.mdpi.com/2308-3425/7/4/53 |
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doaj-7c32d4f3cf10487582bea9ecdb919c042020-11-25T04:10:02ZengMDPI AGJournal of Cardiovascular Development and Disease2308-34252020-11-017535310.3390/jcdd7040053A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal ModelJeffrey E. Cohen0Andrew B. Goldstone1Hanjay Wang2Brendan P. Purcell3Yasuhiro Shudo4John W. MacArthur5Amanda N. Steele6Michael J. Paulsen7Bryan B. Edwards8Chiaka N. Aribeana9Nicholas C. Cheung10Jason A. Burdick11Y. Joseph Woo12Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USADepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USAThe clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy’s potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (<i>n</i> = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure–volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (<i>p</i> = 0.006) and contractility based on the slope of the end-systolic pressure–volume relationship (<i>p</i> = 0.006). NRG-HG also significantly reduced infarct scar size (<i>p</i> = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.https://www.mdpi.com/2308-3425/7/4/53neuregulinhydrogelmyocardial infarctionischemic heart failure |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Jeffrey E. Cohen Andrew B. Goldstone Hanjay Wang Brendan P. Purcell Yasuhiro Shudo John W. MacArthur Amanda N. Steele Michael J. Paulsen Bryan B. Edwards Chiaka N. Aribeana Nicholas C. Cheung Jason A. Burdick Y. Joseph Woo |
| spellingShingle |
Jeffrey E. Cohen Andrew B. Goldstone Hanjay Wang Brendan P. Purcell Yasuhiro Shudo John W. MacArthur Amanda N. Steele Michael J. Paulsen Bryan B. Edwards Chiaka N. Aribeana Nicholas C. Cheung Jason A. Burdick Y. Joseph Woo A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model Journal of Cardiovascular Development and Disease neuregulin hydrogel myocardial infarction ischemic heart failure |
| author_facet |
Jeffrey E. Cohen Andrew B. Goldstone Hanjay Wang Brendan P. Purcell Yasuhiro Shudo John W. MacArthur Amanda N. Steele Michael J. Paulsen Bryan B. Edwards Chiaka N. Aribeana Nicholas C. Cheung Jason A. Burdick Y. Joseph Woo |
| author_sort |
Jeffrey E. Cohen |
| title |
A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model |
| title_short |
A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model |
| title_full |
A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model |
| title_fullStr |
A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model |
| title_full_unstemmed |
A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model |
| title_sort |
bioengineered neuregulin-hydrogel therapy reduces scar size and enhances post-infarct ventricular contractility in an ovine large animal model |
| publisher |
MDPI AG |
| series |
Journal of Cardiovascular Development and Disease |
| issn |
2308-3425 |
| publishDate |
2020-11-01 |
| description |
The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy’s potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (<i>n</i> = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure–volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (<i>p</i> = 0.006) and contractility based on the slope of the end-systolic pressure–volume relationship (<i>p</i> = 0.006). NRG-HG also significantly reduced infarct scar size (<i>p</i> = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI. |
| topic |
neuregulin hydrogel myocardial infarction ischemic heart failure |
| url |
https://www.mdpi.com/2308-3425/7/4/53 |
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