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

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenchao Zhang ◽  
Jianwei Liu ◽  
Yang Fu ◽  
Huifang Ji ◽  
Zheyan Fang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Signaling Pathway ◽  
High Salt ◽  
Angiotensin Receptor ◽  
High Salt Diet ◽  
Salt Diet ◽  
Neprilysin Inhibitor ◽  
Tgf Β1

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 Ⅲ 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-β1/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-β1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.

scholarly journals Early Passive Leg Movement Prevents Against the Development of Heart Failure With Preserved Ejection Fraction in Rats

2021 ◽  
Vol 8 ◽  
Author(s):  
Jian Liu ◽  
Xi-xin Ji ◽  
Yang Fu ◽  
Wen-chao Zhang ◽  
Hui-fang Ji ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Vessel ◽  
Signaling Pathway ◽  
High Salt ◽  
Preserved Ejection Fraction ◽  
High Salt Diet ◽  
Salt Diet ◽  
Leg Movement ◽  
Early Passive ◽  
Tgf Β1

Exercising was reported by several studies to bring great benefits to heart failure with preserved ejection fraction (HFpEF), which reduced the hospitalization and the mortality of heart failure. However, the underlying mechanism of exercising on HFpEF remains unclear. In the present study, we designed and constructed a device that can perform early passive leg movement (ePLM) in rats and further observed whether treatment of ePLM exerts protective effects on HFpEF of rats. Rats were fed with high salt feed to establish an animal model of pre-clinical diastolic dysfunction (PDD), which would eventually develop into HFpEF, and then treated rats with ePLM. We conducted several experiments to evaluate the conditions of heart and blood vessel. The results show that diastolic functions of heart and blood vessel in rats were significantly improved by treatment of ePLM. We also found that pathological injuries of heart and blood vessel were ameliorated after treatment of ePLM. Moreover, treatment of ePLM decreased the protein levels of Collagen type I, Collagen type III, MMP2, and MMP9 in heart and blood vessel, indicating that cardiac and vascular fibrosis were reduced apparently by treatment of ePLM. Further investigation suggested that treatment of ePLM probably inhibit the activation of TGF-β1/Smad3 signaling pathway as well as promote the activation of Akt/eNOS signaling pathway in high salt diet induced HFpEF. In conclusion, treatment of ePLM alleviated high salt diet induced HFpEF by inhibiting fibrosis via suppressing TGF-β1/Smad3 signaling pathway as well as activating Akt/eNOS signaling pathway, implicating treatment of ePLM as a promising novel non-pharmacological approach for HFpEF.

scholarly journals Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
Author(s):  
Yanling Yan ◽  
Jiayan Wang ◽  
Muhammad A. Chaudhry ◽  
Ying Nie ◽  
Shuyan Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Significant Rise ◽  
Protein Carbonylation ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

Heart Failure Therapy in 2016

2016 ◽  
Vol 51 (1) ◽  
pp. 79-82
Author(s):  
Douglas L. Jennings
Keyword(s):  
Heart Failure ◽  
Recent Literature ◽  
Residual Disease ◽  
Angiotensin Receptor ◽  
Heart Failure Therapy ◽  
Call To Action ◽  
Neprilysin Inhibitor ◽  
Drug Regimens ◽  
Contemporary Practice

Heart failure (HF) continues to afflict millions of Americans, resulting in substantial clinical and economic burden to our society. Recent literature has highlighted the role of 2 novel therapies (an angiotensin receptor blocker/neprilysin inhibitor and ivabradine) in further reducing residual disease in HF. Simultaneously, evidence has mounted suggesting that older therapies like digoxin are not effective in contemporary practice and, in fact, may be harmful. This editorial summarizes the most recently published articles pertaining to both new and old HF therapies and provides a call to action to pharmacists on how to shift patients toward effective drug regimens.

Effects of angiotensin receptor neprilysin inhibitor on renal function in patients with heart failure: a systematic review and meta-analysis

2021 ◽  
pp. postgradmedj-2021-140132
Author(s):  
Yuwu Shi ◽  
Yiwen Wang ◽  
Junhong Chen ◽  
Chi Lu ◽  
Haochen Xuan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renal Function ◽  
Ejection Fraction ◽  
Serum Potassium ◽  
Cochrane Library ◽  
Control Group ◽  
Angiotensin Receptor ◽  
Neprilysin Inhibitor ◽  
Patients With Heart Failure ◽  
Angiotensin Receptor Neprilysin Inhibitor

The angiotensin receptor neprilysin inhibitor (ARNI) has been recommended as a first-line treatment in patients with heart failure (HF). However, the effects of ARNI on renal function remain controversial.The PubMed, Embase, the Cochrane Library of Trials and Web of Science were searched in the period from inception to 31 January 2021. Randomised controlled trial, cohort studies and observational studies reporting at least one of renal function indicators were included.In patients with HF with reduced ejection fraction (HFrEF), ARNI did not lead to a significant decrease in estimated glomerular filtration rate (eGFR, p=0.87), and the risk of worsening renal function (WRF) dropped by 11% compared with control group. Though the level of serum creatinine (SCr) and serum potassium had a slight increase (p=0.01; p=0.02), in contrast to the baseline level, but without clinical significance. In patients with HF with preserved ejection fraction (HFpEF), the level of SCr and serum potassium did not have a significant change, and patients with HFpEF assigned to ARNI had a much lower rate of WRF (p=0.0007). In contrast to control group, both patients with HFrEF and HFpEF had a less decrease in eGFR and a lower rate of hyperkalaemia in ARNI group.ARNI did not lead to a significant decrease in eGFR in HFrEF. Compared with control group, ARNI could delay the progression of decrease in eGFR and result in less events of hyperkalaemia in patients with HF. Besides, patients with HFpEF had a lower rate in the events of WRF.

Abstract P097: Angiotensin Receptor Neprilysin Inhibition Improves Arterial Stiffness And Endothelial Function In Heart Failure With Reduced Ejection Fraction

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Sangeetha D Nathaniel ◽  
Shane McGinty ◽  
David G Edwards ◽  
William B Farquhar ◽  
Melissa A Witman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Arterial Stiffness ◽  
Ejection Fraction ◽  
Endothelial Function ◽  
Repeated Measures ◽  
Vascular Function ◽  
Nyha Class ◽  
Angiotensin Receptor ◽  
Reduced Ejection Fraction ◽  
Neprilysin Inhibitor

The mechanisms for the benefits of Angiotensin Receptor Neprilysin inhibitor (ARNi) in heart failure patients with reduced ejection fraction (HFrEF) are likely beyond blood pressure (BP) reduction. Vascular function, a prognostic marker in HFrEF, improves with ARNi in animal models. Improvements in vascular function may contribute to benefits from ARNi in HFrEF; however, this has yet to be demonstrated in humans. The purpose of the study was to test the hypothesis that arterial stiffness and endothelial function would improve after 12 weeks of ARNi in HFrEF. Methods: HFrEF participants with NYHA class II-III were enrolled from local cardiology clinics and completed experimental visits at baseline and 12 weeks later: 13 participants were prescribed ARNi by their cardiologist [62±10 years, Men: 10, BMI: 30±5 kg/m 2 , EF: 28±6 %; Non-ischemic cardiomyopathy (NICM): 8], 10 participants continued on conventional treatment [CON: 60±7 years, Men: 6, BMI: 31±6 kg/m 2 , EF: 31±5 % and NICM: 4; all P=NS]. During each experimental visit, arterial stiffness was assessed via carotid-femoral pulse wave velocity (PWV; Sphygmocor PVx system) and endothelial function by brachial artery flow-mediated dilation (FMD) using standard techniques. Statistical analyses were performed using 2x2 repeated-measures ANOVA. Results: Baseline mean BP (MAP) was similar between ARNi (93±14 mmHg) and CON (85 ± 10 mmHg; P=0.13); MAP tended to decrease after 12 weeks of ARNi (88 ± 11 mmHg; P=0.08) but not CON (90 ± 17 mmHg; P=0.14) (ANOVA interaction P=0.03). PWV tended to be higher at baseline in ARNi (8.8 ± 2.5 m/s) compared to CON (7.0 ± 2.5 m/s; P=0.09); PWV decreased after 12 weeks of ARNi (7.0 ± 1.7 m/s; P<0.01) and was unchanged in CON (7.4 ± 2.4 m/s; P=0.33) (ANOVA interaction P<0.01). When controlling for MAP, the effect of ARNi on PWV remained (P<0.01). At baseline, FMD was similar between ARNi (2.81 ± 2.05%) and CON (4.75 ± 3.75%; P=0.13); however, FMD increased after 12 weeks of ARNi (5.73 ± 1.87%; P<0.001) but not in CON (5.37 ± 3.38%; P=0.33) (ANOVA time P<0.001, interaction P=0.01). Conclusion: ARNi improves arterial stiffness and endothelial function in HFrEF. Understanding the mechanisms of ARNi in HFrEF is crucial as it may pave the way for better interventions in other cardiovascular diseases.

Effects of a chronic high-salt diet on large artery structure: role of endogenous bradykinin

1998 ◽  
Vol 274 (5) ◽  
pp. H1423-H1428 ◽  
Author(s):  
Chohreh Partovian ◽  
Athanase Benetos ◽  
Jean-Pierre Pommiès ◽  
Willy Mischler ◽  
Michel E. Safar
Keyword(s):  
Blood Pressure ◽  
High Salt ◽  
Large Artery ◽  
High Salt Diet ◽  
Salt Diet ◽  
Wky Rats ◽  
Arterial Blood ◽  
Arterial Structure ◽  
Hoe 140

Bradykinin activity could explain the blood pressure increase during NaCl loading in hypertensive animals, but its contribution on vascular structure was not evaluated. We determined cardiac mass and large artery structure after a chronic, 4-mo, high-salt diet in combination with bradykinin B2-receptor blockade by Hoe-140. Four-week-old rats were divided into eight groups according to strain [spontaneously hypertensive rats (SHR) vs. Wistar-Kyoto (WKY) rats], diet (0.4 vs. 7% NaCl), and treatment (Hoe-140 vs. placebo). In WKY rats, a high-salt diet significantly increased intra-arterial blood pressure with minor changes in arterial structure independently of Hoe-140. In SHR, blood pressure remained stable but 1) the high-salt diet was significantly associated with cardiovascular hypertrophy and increased arterial elastin and collagen, and 2) Hoe-140 alone induced carotid hypertrophy. A high-salt diet plus Hoe-140 acted synergistically on carotid hypertrophy and elastin content in SHR, suggesting that the role of endogenous bradykinin on arterial structure was amplified in the presence of a high-salt diet.

Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats

1994 ◽  
Vol 267 (6) ◽  
pp. H2471-H2482 ◽  
Author(s):  
M. Inoko ◽  
Y. Kihara ◽  
I. Morii ◽  
H. Fujiwara ◽  
S. Sasayama
Keyword(s):  
Heart Failure ◽  
Systolic Pressure ◽  
Myocardial Necrosis ◽  
Compensatory Hypertrophy ◽  
High Salt ◽  
High Salt Diet ◽  
Tension Development ◽  
Salt Diet ◽  
The Right

To establish an experimental model for studying a specific transitional stage for compensatory hypertrophy to heart failure, we studied the pathophysiology of the left ventricle (LV) in Dahl salt-sensitive (DS) rats fed a high-salt diet. DS rats fed an 8% NaCl diet after the age of 6 wk developed concentric LV hypertrophy at 11 wk, followed by marked LV dilatation at 15-20 wk. During the latter stage, the DS rats showed labored respiration with LV global hypokinesis. All the DS rats died within 1 wk by massive pulmonary congestion. The dissected left ventricles revealed chamber dilatation and a marked increase in mass without myocardial necrosis. In contrast, corresponding Dahl salt-resistant (DR) rats fed the same diet showed neither mortality nor any of these pathological changes. The in vivo LV end-systolic pressure-volume relationship shifted to the right with a less steep slope in the failing DS rats compared with that in age-matched DR rats. Isometric contractions of LV papillary muscles isolated from these DS rats showed reduced tension development in the failing stage, but normal tension development in the hypertrophied stage. In conclusion, the DS rat fed a high-salt diet is a useful model showing rapidly developing congestive heart failure, in which the transition from compensatory hypertrophy to decompensatory dilatation of LV is easily and consistently manifested.

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