<scp>LCZ696</scp>, an angiotensin receptor–neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin‐induced diabetic mice

Suematsu, Yasunori; Miura, Shin‐ichiro; Goto, Masaki; Matsuo, Yoshino; Arimura, Tadaaki; Kuwano, Takashi; Imaizumi, Satoshi; Iwata, Atsushi; Yahiro, Eiji; Saku, Keijiro

doi:10.1002/ejhf.474

Cited by 134 publications

(96 citation statements)

References 31 publications

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“…It has been found that biomarkers for cardiac remodeling show no significant changes in HFpEF or HFrEF [35]. The reason for this might be that cardiac fibrosis contributes to the process of both HFpEF [36] and HFrEF [37]. Because CCN1 is quite important in cardiac remodeling, it is Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry reasonable that the level of CCN1 increases both in HFpEF and HFrEF.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Serum Cysteine-Rich Protein 61 in Patients with Acute Heart Failure

Zhao

Zhang

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cyr61-cysteine-rich protein 61 (CCN1/CYR61) is a multifunctional matricellular protein involved in the regulation of fibrogenesis. Animal experiments have demonstrated that CCN1 can inhibit cardiac fibrosis in cardiac hypertrophy. However, no study has been conducted to assess the relation between serum CCN1 and prognosis of acute heart failure (AHF). Methods: We measured the serum CCN1 levels of 183 patients with AHF, and the patients were followed up for 6 months. The associations between CCN1 levels and some clinical covariates, especially left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), atrial fibrillation and age, were estimated. The AHF patients were followed up for 6 months. The endpoint was all-cause mortality. Kaplan-Meier curve analysis and multivariable Cox proportional hazards analysis were employed to evaluate the prognostic ability of CCN1. We used calibration, discrimination and reclassification to assess the mortality risk prediction of adding CCN1. Results: Serum CCN1 concentrations in AHF patients were significantly increased compared with those in individuals without AHF (237 pg/ml vs. 124.8 pg/ml, p< 0.001). CCN1 level was associated with the level of NT-proBNP (r=0.349, p< 0.001) and was not affected by LVEF, eGFR, age or atrial fibrillation in AHF patients. Importantly, Kaplan-Meier curve analysis illustrated that the AHF patients with serum CCN1 level > 260 pg/ ml had a lower survival rate (p< 0.001). Multivariate Cox hazard analysis suggests that CCN1 functions as an independent predictor of mortality for AHF patients (LgCCN1, hazard ratio 5.825, 95% confidence interval: 1.828-18.566, p=0.003). In addition, the inclusion of CCN1 in the model with NT-proBNP significantly improved the C-statistic for predicting death (0.758, p< 0.001). The integrated discrimination index was 0.019 (p< 0.001), and the net reclassification index increased significantly after addition of CCN1 (23.9%, p=0.0179). Conclusions: CCN1 is strongly predictive of 6-month mortality in patients with AHF, suggesting serum CCN1 as a promising candidate prognostic biomarker for AHF patients.

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Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Serum Cysteine-Rich Protein 61 in Patients with Acute Heart Failure

Zhao

Zhang

Liu

et al. 2018

Cell Physiol Biochem

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“…In addition, we previously indicated that LCZ696-induced improvement of cardiac function in the HFrEF model in diabetic mice may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696. 6 In this study, we found that the suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The inhibition of the degradation of NPs has been evaluated for potential therapeutic benefits.…”

Section: Discussionmentioning

confidence: 53%

“…5 In addition, we recently reported that LCZ696 improved cardiac function with the reduction of fibrosis in a model of HFrEF (HF with reduced ejection fraction) in diabetic mice. 6 Neprilysin is responsible for the degradation of several vasoactive peptides including atrial and brain natriuretic peptides (NPs) (ANP and BNP). 7 These peptides block the negative cardiovascular effects of Ang II and aldosterone (Ald) in HF patients, including sodium retention, vasoconstriction, hypertrophy and endothelial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line

et al. 2016

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A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT receptor was greater than that of valsartan alone in an AT receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3β-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT receptor-induced Ald synthesis in human adrenocortical cells.

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“…Suematsu et al used tenfold higher dosages of valsartan and LCZ696, compared with Bai et al, in streptozotocin-treated diabetic mice, after myocardial reperfusion injury [26]. At the end of the 4-week treatment period, only valsartan-treated animals had a significantly lower blood pressure than vehicle-treated animals.…”

Section: Animal Studiesmentioning

confidence: 99%

From ARB to ARNI in Cardiovascular Control

et al. 2016

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Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition (‘ARNI’) with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria were reduced particularly in diabetic patients. The exact underlying mechanism remains unknown, but may involve improved renal haemodynamics and reduced glomerulosclerosis, e.g. related to a rise in natriuretic peptide levels. However, the assays of these peptides are hampered by methodological artefacts. Moreover, since sacubitrilat is largely renally cleared, drug accumulation may occur in patients with impaired renal function and thus hypotension is a potential side effect in patients with chronic kidney disease. Further caution is warranted since neprilysin also degrades endothelin-1 and amyloid beta in animal models. Accumulation of the latter may increase the risk of Alzheimer’s disease.

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LCZ696, an angiotensin receptor–neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin‐induced diabetic mice

Cited by 134 publications

References 31 publications

Prognostic Significance of Serum Cysteine-Rich Protein 61 in Patients with Acute Heart Failure

Prognostic Significance of Serum Cysteine-Rich Protein 61 in Patients with Acute Heart Failure

The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line

From ARB to ARNI in Cardiovascular Control

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