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Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats.

ABSTRACT: Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type ? collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-?1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-?1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.

SUBMITTER: Zhang W

PROVIDER: S-EPMC7841406 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats.

Zhang Wenchao W Liu Jianwei J Fu Yang Y Ji Huifang H Fang Zheyan Z Zhou Wanming W Fan Huimin H Zhang Yingxuan Y Liao Yan Y Yang Ting T Wang Xiaolin X Yuan Wanwan W Chen Xiaoshu X Dong Yi-Fei YF

Frontiers in pharmacology 20210114

Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated th ...[more]

PMID: 33519461

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Project description:Introduction Heart failure with preserved ejection fraction (HFpEF), which is a common co-morbidity in patients with maintenance hemodialysis (MHD), results in substantial mortality and morbidity. However, there are still no effective therapeutic drugs available for HFpEF currently. Sacubitril/valsartan has been shown to significantly improve clinical outcomes and reverse myocardial remodeling among patients with heart failure with reduced ejection fraction (HFrEF). The effect of sacubitril/valsartan in MHD patients with HFpEF remains unclear. Our study was designed to assess the efficacy and safety of sacubitril/valsartan in MHD patients with HFpEF. Methods A total of 247 MHD patients with HFpEF treated with sacubitril/valsartan were included in this retrospective study. Patients were followed up regularly after medication treatment. The alterations in clinical, biochemical, and echocardiographic parameters before and after taking sacubitril/valsartan were collected. In addition, the safety of the sacubitril/valsartan treatment was also assessed. Among those 247 patients with MHD, 211 patients were already in treatment with angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) before being treated with sacubitril/valsartan. We also performed an analysis to compare the differences between the 211 patients who had previously received ACEi/ARB treatment and the 36 patients who were sacubitril/valsartan naive. Results Among those 247 patients with MHD, compared with baseline levels, systolic blood pressure (BP) (149.7 ± 23.6 vs. 137.2 ± 21.0 mmHg, P < 0.001), diastolic BP (90.2 ± 16.1 vs. 84.5 ± 14.1 mmHg, P < 0.001), heart rate (83.5 ± 12.5 vs. 80.0 ± 8.7 bpm, P < 0.001), N-terminal B-type natriuretic peptide precursor (NT-proBNP) [29125.0 (11474.5, 68532.0) vs. 12561.3 (4035.0, 37575.0) pg/ml, P < 0.001], and cardiac troponin I [0.044 (0.025, 0.078) vs. 0.0370 (0.020, 0.064) μg/L, P = 0.009] were markedly decreased after treatment with sacubitril/valsartan. New York Heart Association (NYHA) functional class showed a notable trend of improvement after 3–12 months of follow-up. Echocardiographic parameters including left ventricular posterior wall thickness (LVPWT) (11.8 ± 2.0 vs. 10.8 ± 1.9 mm, P < 0.001), intraventricular septal thickness in diastole (11.8 ± 2.0 vs. 11.2 ± 2.0 mm, P < 0.001), left ventricular end-diastolic diameter (53.8 ± 6.9 vs. 51.2 ± 7.1 mm, P < 0.001), left atrial diameter (LAD) (40.5 ± 6.2 vs. 37.2 ± 7.2 mm, P < 0.001), left ventricular end-diastolic volume (LVEDV) [143.0 (111.5, 174.0) vs. 130.0 (105.0, 163.0) ml, P < 0.001], left ventricular end-systolic volume (LVESV) [57.0 (43.0, 82.5) vs. 48.0 (38.0, 74.0) ml, P < 0.001], and pulmonary arterial systolic pressure [39.0 (30.5, 50.0) vs. 28.0 (21.0, 37.5) mmHg, P < 0.001] were significantly reduced after initiating the treatment of sacubitril/valsartan. The parameters of left ventricular diastolic function including E/A ratio [0.8 (0.7, 1.3) vs. 0.9 (0.8, 1.3), P = 0.008], maximal tricuspid regurgitation velocity [2.7 (2.5, 3.2) vs. 2.4 (2.0, 2.8) m/s, P < 0.001], septal e’wave velocity (8.0 ± 0.6 vs. 8.2 ± 0.5 cm/s, P = 0.001), lateral e’ wave velocity (9.9 ± 0.8 vs. 10.2 ± 0.7 cm/s, P < 0.001), E/e’ [8.3 (6.4, 11.8) vs. 7.2 (6.1, 8.9), P < 0.001], and left atrial volume index (37.9 ± 4.2 vs. 36.4 ± 4.1 ml/m2, P < 0.001) were significantly improved by sacubitril/valsartan. Among 211 patients who were already in treatment with ACEi/ARB and 36 patients who were sacubitril/valsartan naive, the improvement of cardiac function demonstrated by clinical outcomes and echocardiographic parameters were similar to the previous one of the 247 MHD patients with HFpEF. During the follow-up, none of the patients showed severe adverse drug reactions. Conclusion Our study suggested that sacubitril/valsartan treatment in MHD patients with HFpEF was effective and safe.

Project description:ObjectiveTo evaluate the impact of sacubitril/valsartan on blood pressure (BP), ventricular structure, and myocardial fibrosis compared with valsartan in perimenopausal hypertensive women.MethodsThis prospective, randomized, actively controlled, open-label study included 292 women with perimenopausal hypertension. They were randomly divided into two groups: sacubitril/valsartan 200 mg once daily and valsartan 160 mg once daily for 24 weeks. The relevant indicators of ambulatory BP, echocardiography, and myocardial fibrosis regulation were assessed at baseline and at 24 weeks.ResultsThe 24-h mean SBP after 24 weeks of treatment was 120.08 ± 10.47 mmHg in the sacubitril/valsartan group versus 121.00 ± 9.76 mmHg in the valsartan group ( P = 0.457). After 24 weeks of treatment, there was no difference in central SBP between the sacubitril/valsartan and valsartan groups (117.17 ± 11.63 versus 116.38 ± 11.58, P = 0.568). LVMI in the sacubitril/valsartan group was lower than that in the valsartan group at week 24 ( P = 0.009). LVMI decreased by 7.23 g/m 2 from the baseline in the sacubitril/valsartan group and 3.70 g/m 2 in the valsartan group at 24 weeks ( P = 0.000 versus 0.017). A statistically significant difference in LVMI between the two groups was observed at 24 weeks after adjusting for the baseline LVMI ( P = 0.001). The levels of α-smooth muscle actin (α-SMA), connective tissue growth factor (CT-GF) and transforming growth factor-β (TGF-β) were reduced in the sacubitril/valsartan group compared with the baseline ( P = 0.000, 0.005, and 0.000). LVMI between the two groups was statistically significant at 24 weeks after correcting for confounding factors 24-h mean SBP and 24-h mean DBP ( P = 0.005). The LVMI, serum TGF-β, α-SMA, and CT-GF remained statistically significant between the two groups after further correcting the factors of age, BMI, and sex hormone levels ( P < 0.05).ConclusionSacubitril/valsartan could reverse ventricular remodeling more effectively than valsartan. The different effects of these two therapies on ventricular remodeling in perimenopausal hypertensive women might be because of their different effects on the down-regulation of fibrosis-related factors.

Project description:BackgroundDiffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor-neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD.MethodsRole of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan.DiscussionREVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through a multimodal manner integrating complementary CMR and biomarkers into the conventional care approach.Clinical Trial Registration: ClinicalTrials.gov, identifier, NCT03553810.

Dataset Information

Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats.

Publications

Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats.

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