Efficacy of Neprilysin Inhibition in Women With HFpEF: Beyond Phenotypes and Natriuretic Peptides.
Ontology highlight
ABSTRACT:
SUBMITTER: Cooper LB
PROVIDER: S-EPMC7891855 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Efficacy of Neprilysin Inhibition in Women With HFpEF: Beyond Phenotypes and Natriuretic Peptides.
Cooper Lauren B LB Cotugno Annunziata A deFilippi Christopher C
Circulation 20210215 7
Similar Datasets
Project description:Heart failure (HF) is a significant cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) is a complex syndrome, often participated by several cardiac and extracardiac conditions, including chronic kidney disease, pulmonary disease, anaemia and advanced age. Circulating biomarkers reflecting pathophysiological pathways involved in HFpEF development and progression may assist clinicians in early diagnosis and management of this condition. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload and in response to activation of neuro-endocrine-immune system. The relevance of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification has been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the value of NPs to guide HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, predicting outcome independently from NPs. In this review, some novel biomarkers are being tested in such clinical scenario, more tightly linked to specific pathophysiological processes of cardiac damage.
| S-EPMC9409788 | biostudies-literature
Project description:ObjectivesThe aim of this study was to determine if the atrial natriuretic peptide (ANP) precursor proANP is biologically active compared with ANP and B-type natriuretic peptide (BNP).BackgroundProANP is produced in the atria and processed to ANP and activates the guanylyl cyclase receptor-A (GC-A) and its second messenger, cyclic guanosine monophosphate (cGMP). ProANP is found in the human circulation, but its bioavailability is undefined.MethodsThe in vivo actions of proANP compared with ANP, BNP, and placebo were investigated in normal canines (667 pmol/kg, n = 5/group). cGMP activation in human embryonic kidney 293 cells expressing GC-A or guanylyl cyclase receptor-B was also determined. ProANP processing and degradation were observed in serum from normal subjects (n = 13) and patients with heart failure (n = 14) ex vivo.ResultsProANP had greater diuretic and natriuretic properties, with more sustained renal tubular actions, compared with ANP and BNP in vivo in normal canines, including marked renal vasodilation not observed with ANP or BNP. ProANP also resulted in greater and more prolonged cardiac unloading than ANP but much less hypotensive effects than BNP. ProANP stimulated cGMP generation by GC-A as much as ANP. ProANP was processed to ANP in serum from normal control subjects and patients with heart failure ex vivo.ConclusionsProANP represents a novel activator of GC-A with enhanced diuretic, natriuretic, and renal vasodilating properties, and it may represent a key circulating natriuretic peptide in cardiorenal and blood pressure homeostasis. These results support the concepts that proANP may be a potential innovative therapeutic beyond ANP or BNP for cardiorenal diseases, including heart failure.
| S-EPMC4568029 | biostudies-literature
Project description:BackgroundAlthough N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a strong relationship with incident cardiovascular disease (CVD), few studies have examined whether NT-proBNP adds to risk prediction algorithms, particularly in women.ObjectivesThis study sought to evaluate the relationship between NT-proBNP and incident CVD in women.MethodsUsing a prospective case-cohort within the WHI (Women's Health Initiative) observational study, we selected 1,821 incident cases of CVD (746 myocardial infarctions, 754 ischemic strokes, 160 hemorrhagic strokes, and 161 other cardiovascular [CV] deaths) and a randomly selected reference cohort of 1,992 women without CVD at baseline.ResultsMedian levels of NT-proBNP were higher at study entry among incident cases (120.3 ng/l [interquartile range (IQR): 68.1 to 219.5 ng/l]) than among control subjects (100.4 ng/l [IQR: 59.7 to 172.6 ng/l]; p < 0.0001). Women in the highest quartile of NT-proBNP (≥140.8 ng/l) were at 53% increased risk of CVD versus those in the lowest quartile after adjusting for traditional risk factors (1.53 [95% confidence interval (CI): 1.21 to 1.94]; p for trend <0.0001). Similar associations were observed after adjustment for Reynolds Risk Score covariables (1.53 [95% CI: 1.20 to 1.95]; p for trend <0.0001); the association remained in separate analyses of CV death (2.66 [95% CI: 1.48 to 4.81]; p for trend <0.0001), myocardial infarction (1.39 [95% CI: 1.02 to 1.88]; p for trend = 0.008), and stroke (1.60 [95% CI: 1.22 to 2.11]; p for trend <0.0001). When added to traditional risk covariables, NT-proBNP improved the c-statistic (0.765 to 0.774; p = 0.0003), categorical net reclassification (0.08; p < 0.0001), and integrated discrimination (0.0105; p < 0.0001). Similar results were observed when NT-proBNP was added to the Reynolds Risk Score.ConclusionsIn this multiethnic cohort of women with numerous CV events, NT-proBNP modestly improved measures of CVD risk prediction.
| S-EPMC4294182 | biostudies-literature
Project description:Natriuretic peptides are cardiac-derived hormones with a range of protective functions, including natriuresis, diuresis, vasodilation, lusitropy, lipolysis, weight loss, and improved insulin sensitivity. Their actions are mediated through membrane-bound guanylyl cyclases that lead to production of the intracellular second-messenger cyclic guanosine monophosphate. A growing body of evidence demonstrates that genetic and acquired deficiencies of the natriuretic peptide system can promote hypertension, cardiac hypertrophy, obesity, diabetes mellitus, the metabolic syndrome, and heart failure. Clinically, natriuretic peptides are robust diagnostic and prognostic markers, and augmenting natriuretic peptides is a target for therapeutic strategies in cardiometabolic disease. This review will summarize current understanding and highlight novel aspects of natriuretic peptide biology.
| S-EPMC4893202 | biostudies-literature
Project description:Endogenous natriuretic peptides serve as potent activators of particulate guanylyl cyclase receptors and the second messenger cGMP. Natriuretic peptides are essential in maintenance of volume homeostasis, and can be of myocardial, renal and endothelial origin. Advances in peptide engineering have permitted the ability to pursue highly innovative drug discovery strategies. This has resulted in designer natriuretic peptides that go beyond native peptides in efficacy, specificity, and resistance to enzymatic degradation. Together with recent improvements in peptide delivery systems, which have improved bioavailability, further advances in this field have been made. Therefore, designer natriuretic peptides with pleotropic actions together with strategies of chronic delivery have provided an unparalleled opportunity for the treatment of cardiovascular disease. In this review, we report the conceptual framework of peptide engineering of the natriuretic peptides that resulted in designer peptides for cardiovascular disease. We specifically provide an update on those currently in clinical trials for heart failure and hypertension, which include Cenderitide, ANX042 and ZD100.
| S-EPMC5423722 | biostudies-literature
Project description:Neprilysin (NEP), an ectoenzyme that modulates inflammation by degrading neuropeptides, was recently identified in the human corneal epithelium. The cornea expresses many NEP substrates, but the function of NEP in homeostatic maintenance and wound healing of the cornea is unknown. We therefore investigated the role of this enzyme under naive and injured conditions using NEP-deficient (NEP-/-) and wild type (WT) control mice. In vivo ocular surface imaging and histological analysis of corneal tissue showed no differences in limbal vasculature or corneal anatomy between naive NEP-/- and WT mice. Histological examination revealed increased corneal innervation in NEP-/- mice. In an alkali burn model of corneal injury, corneal wound healing was significantly accelerated in NEP-/- mice compared to WT controls 3 days after injury. Daily intraperitoneal administration of the NEP inhibitor thiorphan also accelerated corneal wound healing after alkali injury in WT mice. Collectively, our data identify a previously unknown role of NEP in the cornea, in which pharmacologic inhibition of its activity may provide a novel therapeutic option for patients with corneal injury.
| S-EPMC6158251 | biostudies-literature
Project description:Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin-angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population.
| S-EPMC4425478 | biostudies-literature
Project description:Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water-salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.
| S-EPMC6719167 | biostudies-literature
Project description:Besides the relevant role of brain-type natriuretic peptide (BNP) as biomarker of cardioembolic strokes, new experimental evidences suggest that this peptide may mediate neuroprotective effects. In this study, we have evaluated for the first time the clinical association between BNP (by means of proBNP) and good outcome in ischemic stroke patients, and analyzed the effect of blood BNP increase in an ischemic animal model. A retrospective study with 2 different cohorts (262 patients in cohort I and 610 in cohort II) from the same prospective stroke registry was performed. proBNP concentration was analyzed within the first 12 hours from stroke onset. The primary predictor variable was functional outcome evaluated by modified Rankin Scale at 3 months. For the experimental study, BNP pretreatment was tested in an ischemic animal model subjected to a transient occlusion of the cerebral artery, and the infarct volume and sensorimotor deficit were evaluated for 14 days. Cardioembolic strokes presented a positive correlation between proBNP concentration and modified Rankin Scale at 3 months; however, noncardioembolic strokes presented a negative correlation. In the logistic regression analysis, noncardioembolic strokes with concentrations of proBNP ≥340 pg/mL were associated with a good outcome. In line with these clinical findings, the experimental study revealed that those BNP pretreated animals presented a reduction on infarct volumes at 24 hours and functional recovery at days 7 and 14 compared with the control groups. These clinical and experimental evidences support the potential role of BNP as a protective factor against cerebral ischemia.
| S-EPMC5779043 | biostudies-literature
Project description:Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
| S-EPMC4800749 | biostudies-literature