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Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury

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Abstract
Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 +/- 13.8 mu L versus 525.1 +/- 23.6 mu L; p < 0.05), while valsartan did not (471.2 +/- 8.9 mu L; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 +/- 2.7 mu m vs. 48.8 +/- 7.5 mu m; p < 0.05). Transforming growth factor-beta and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.
Author(s)
강근형강덕현송나아름송종민이사민지은혜최경희황효숙
Issued Date
2021
Type
Article
Keyword
angiotensin receptor antagonistsheart failureheart ventriclesmitral valve insufficiencyneprilysin
DOI
10.3390/ijms22168598
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8212
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_27644b4b854545539b16efb124f3caca&amp;context=PC&amp;vid=ULSAN&amp;lang=ko_KR&amp;search_scope=default_scope&amp;adaptor=primo_central_multiple_fe&amp;tab=default_tab&amp;query=any,contains,Effect%20of%20Neprilysin%20Inhibition%20for%20Ischemic%20Mitral%20Regurgitation%20after%20Myocardial%20Injury&amp;offset=0&amp;pcAvailability=true
Publisher
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Location
스위스
Language
영어
ISSN
1422-0067
Citation Volume
22
Citation Number
16
Citation Start Page
0
Citation End Page
0
Appears in Collections:
Medicine > Medicine
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