scholarly journals LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates diabetic cardiomyopathy by inhibiting inflammation, oxidative stress and apoptosis

2019 ◽  
Vol 244 (12) ◽  
pp. 1028-1039 ◽  
Author(s):  
Qing Ge ◽  
Li Zhao ◽  
Xiao-Min Ren ◽  
Peng Ye ◽  
Zuo-Ying Hu
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Diabetic Cardiomyopathy ◽  
Ventricular Remodeling ◽  
Heart Tissue ◽  
Inflammatory Factors ◽  
Diabetic Mice ◽  
Angiotensin Receptor ◽  
Neprilysin Inhibitor ◽  
Angiotensin Receptor Neprilysin Inhibitor

Diabetic cardiomyopathy, which refers to the destruction of the structure and function of the heart, is the primary cause of heart failure due to diabetes. LCZ696 is the first angiotensin receptor-neprilysin inhibitor (ARNi) to be used clinically. Our study investigated the role played by LCZ696 during diabetic cardiomyopathy and explored the potential mechanisms underlying these effects. Diabetes was induced by injecting streptozotocin intraperitoneally into mice, and the mice were then divided randomly into two groups: one group was treated with LCZ696 (60 mg/kg/d) for 16 weeks, and the other received no treatment. The H9C2 cardiomyoblast cell line was treated with LCZ696 under high-glucose (HG) conditions. The levels of apoptotic (Bax, Bcl-2 and cleaved caspase-3) and pro-inflammatory factors [nuclear factor (NF)-κB, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (MAPK)] were assessed in heart tissues from diabetic and normal mice and in H9C2 cells. The heart tissue structures and cardiac functions of diabetic mice were compared with those of normal mice, using histological and echocardiographic analyses. The results showed that LCZ696 inhibits the nuclear transfer of NF-κB and JNK/p38MAPK phosphorylation, and mitigates inflammation and apoptosis in diabetic mice and H9C2 cardiomyocytes under HG conditions. The histological and echocardiographic data showed that compared with untreated diabetic mice, diabetic mice treated with LCZ696 exhibited improved ventricular remodeling and cardiac function. LCZ696 also ameliorated oxidative stress in both vivo and vitro. In conclusion, LCZ696 improved diabetic cardiomyopathy by reducing cardiac inflammation, oxidative stress, and apoptosis. Impact statement Diabetic cardiomyopathy (DCM) is an important cause of heart failure in patients with diabetes, resulting in increased morbidity and mortality. LCZ696, which was studied here, is a novel drug for the treatment of heart failure. The latest research reports that LCZ696 is more effective for preventing heart failure than valsartan alone. However, little research has been performed examining the effects of LCZ696 on DCM. This study was designed to examine the role played by LCZ696 during DCM and the potential mechanisms underlying these effects, which may provide the basis for a new therapeutic strategy for DCM.

Abstract 19363: Prevention of Progressive Worsening of Heart Failure Over Time With The Angiotensin-receptor Neprilysin Inhibitor Sacubitril/valsartan (lcz696)

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
John McMurray ◽  
Pardeep Jhund ◽  
Jianjian Gong ◽  
Jean Rouleau ◽  
Martin Lefkowitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pharmacological Therapy ◽  
Number Needed To Treat ◽  
Angiotensin Receptor ◽  
Class Iii ◽  
Mineralocorticoid Receptor Antagonist ◽  
Prospective Comparison ◽  
Neprilysin Inhibitor ◽  
Angiotensin Receptor Neprilysin Inhibitor ◽  
Over Time

Background: The aim of this analysis was to examine the effect of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696), compared with enalapril, on progressive worsening over time in patients with heart failure and reduced ejection fraction (HF-REF) enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidly in Heart Failure trial (PARADIGM-HF). Methods: In PARADIGM-HF, 4212 patients were randomized to enalapril and 4187 to sacubitril/valsartan. The primary outcome was the composite of cardiovascular (CV) death or hospitalization for heart failure (HF). To make a more comprehensive evaluation of HF worsening over time, we analysed the broader composite of CV death, HF hospitalization, emergency department visit for HF or intensification of therapy for HF (as time-to-first event) using the Kaplan-Meier (KM) method. Results: At baseline, 71% of patients were in NYHA functional class II and 24% in class III. Their mean LVEF was 27% and 93% were treated with a beta-blocker and 56% with a mineralocorticoid receptor antagonist. The median duration of follow-up was 27 months. The 1, 2 and 3 year KM rates for the composite outcome in the enalapril group were 16.5 (95% CI 15.5, 17.7)%, 27.6 (26.2, 29.1) and 34.8 (33.1-36.6)%, respectively. The corresponding rates in the sacubitril/valsartan group were 13.4 (12.4, 14.5), 22.1 (20.8, 23.4) and 29.5 (27.9, 31.2)%, respectively. Overall 1275 enalapril treated and 1038 sacubitril/valsartan treated patients had an event, giving a hazard ratio 0.79 (95% CI 0.73, 0.86), p<0.0001. Over the course of the trial, 55 fewer patients per 1000 treated with sacubitril/valsartan, compared with enalapril, experienced worsening (number needed to treat = 18). Conclusions: Even in patients with predominantly mild symptoms, well treated with evidence-based pharmacological therapy, worsening of HF over time was common, with more than a third of patients exhibiting progression within 3 years. The ARNI sacubitril/valsartan led to clinically important relative and absolute reductions in progressive worsening, compared with enalapril.

Shift of conventional paradigm of heart failure treatment: from angiotensin receptor neprilysin inhibitor to sodium–glucose co-transporter 2 inhibitors?

2021 ◽  
Vol 17 (3) ◽  
pp. 497-506
Author(s):  
Alexander E Berezin ◽  
Alexander A Berezin
Keyword(s):  
Heart Failure ◽  
Wide Spectrum ◽  
Large Body ◽  
Renin Angiotensin System ◽  
Angiotensin Receptor ◽  
Heart Failure Treatment ◽  
Angiotensin System ◽  
Reduced Ejection Fraction ◽  
Neprilysin Inhibitor ◽  
Angiotensin Receptor Neprilysin Inhibitor

Current clinical guidelines for heart failure (HF) contain a brand new therapeutic strategy for HF with reduced ejection fraction (HFrEF), which is based on neurohumoral modulation through the use of angiotensin receptor neprilysin inhibitors. There is a large body of evidence for the fact that sodium-glucose co-transporter 2 inhibitors may significantly improve all-cause mortality, cardiovascular mortality and hospitalization for HF in patients with HFrEF who received renin–angiotensin system blockers including angiotensin receptor neprilysin inhibitors, β-blockers and mineralocorticoid receptor antagonists. The review discusses that sodium-glucose co-transporter 2 inhibitors have a wide spectrum of favorable molecular effects and contribute to tissue protection, improving survival in HFrEF patients.

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.

scholarly journals Initiation of Angiotensin Receptor-Neprilysin Inhibitor in Heart Failure With Low Cardiac Output

2019 ◽  
Vol 74 (18) ◽  
pp. 2326-2327 ◽  
Author(s):  
Trejeeve Martyn ◽  
Kathleen D. Faulkenberg ◽  
Dmitry M. Yaranov ◽  
Chonyang L. Albert ◽  
Colleen Hutchinson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Output ◽  
Angiotensin Receptor ◽  
Low Cardiac Output ◽  
Neprilysin Inhibitor ◽  
Angiotensin Receptor Neprilysin Inhibitor
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