Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury.

Sahmin Lee,Hyo-Sook Hwang,Jong-Min Song,Duk-Hyun Kang,Kyoung-Hee Choi,Eunhye Ji,Naaleum Song,Geun-Hyung Kang

doi:10.3390/ijms22168598

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 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; 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 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-β 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.

Highlights

After myocardial infarction (MI), tethering and fibrosis of mitral leaflets stimulate functional mitral regurgitation (MR), resulting in high morbidity of heart failure (HF) and cardiac mortality [1,2,3,4,5,6,7,8]
As secondary functional MR usually develops as a result of left ventricular (LV) dysfunction [1,6], medications for HF such as beta blockers, angiotensinconverting-enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) are the mainstay of medical therapy for functional MR [9,10]
Randomization, all of 31 experimental rats survived well and there was no significant and randomization, all of 31 experimental rats survived well and there was no significant difference in serial serial changes changesofofbody bodyweight weightbetween between three groups; LCZ696 treatment, difference in thethe three groups; LCZ696 treatment, valsartan treatment, and control group (Figure valsartan treatment, and MR control group (Figure 1F)

Summary

Introduction

After myocardial infarction (MI), tethering and fibrosis of mitral leaflets stimulate functional mitral regurgitation (MR), resulting in high morbidity of heart failure (HF) and cardiac mortality [1,2,3,4,5,6,7,8]. Post-MI changes in the mitral valve (MV) are associated with LV remodeling, and with an excessive endothelial-to-mesenchymal transition (EndoMT) by transforming growth factor-β (TGF-β) overexpression [13,14]. Fibrotic remodeling and thickened by transforming growth factor-β (TGF-β) overexpression [13,14]. Fibrotic remodeling and thickened leaflet of MV make leaflet area insufficient and cause inadequate adaptation, which results in coaptation failure of mitral leaflets and facilitates functional MR [15,16,17,18,19,20].

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