Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure

Oatmen, Kelsie E.; Zile, Michael R.; Burnett, John C.; Spinale, Francis G.

doi:10.1001/jamacardio.2018.3789

Cited by 13 publications

(11 citation statements)

References 174 publications

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“…A similar dynamic course could be confirmed with our data. However, NEP cleaves a broad spectrum of peptides; thus, it was suggested that the net effect of NEPi would be more complex depending on the relative dominance of the respective substrates 14 . The affinity of NEP to ADM is assumedly even higher than to BNP 15 .…”

Section: Discussionmentioning

confidence: 99%

“…However, NEP cleaves a broad spectrum of peptides; thus, it was suggested that the net effect of NEPi would be more complex depending on the relative dominance of the respective substrates. 14 The affinity of NEP to ADM is assumedly even higher than to BNP. 15 While BNP increased by 20% from baseline levels in the PARADIGM-HF cohort, 13 concentrations of bio-ADM and MR-proADM nearly doubled and remained stable over 2 years after the initiation of ARNi in our study.…”

Section: T a B L E 2 Correlation Between Bio-adm Mrmentioning

confidence: 99%

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Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Arfsten

Goliasch

Bartko

et al. 2020

Brit J Clinical Pharma

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The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi. Methods: Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up. Results: Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0

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Section: Discussionmentioning

confidence: 99%

Section: T a B L E 2 Correlation Between Bio-adm Mrmentioning

confidence: 99%

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Arfsten

Goliasch

Bartko

et al. 2020

Brit J Clinical Pharma

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“…Recently, an effective new heart failure drug was developed in which the ARB valsartan was combined with the neprilysin inhibitor sacubitril (21), which blocks the degradation of endogenous natriuretic peptides, leading to an increase in cyclic nucleotides in target tissues, particularly in the kidney (15). The combination of these two drugs proved to be more efficacious than RAAS blockade alone in preventing the progression of heart failure (21,25). Although the effects of AT1R blockade on the vasculature have long been appreciated, the roles of cardiac AT1Rs in development of heart failure are much less well understood.…”

Section: Introductionmentioning

confidence: 99%

Reversal of heart failure in a chemogenetic model of persistent cardiac redox stress

Sorrentino

Steinhorn

Troncone

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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We previously described a novel “chemogenetic” animal model of heart failure that recapitulates a characteristic feature commonly found in human heart failure: chronic oxidative stress. This heart failure model uses a chemogenetic approach to activate a recombinant yeast d-amino acid oxidase in rat hearts in vivo to generate oxidative stress, which then rapidly leads to the development of a dilated cardiomyopathy. Here we apply this new model to drug testing by studying its response to treatment with the angiotensin II (ANG II) receptor blocker valsartan, administered either alone or with the neprilysin inhibitor sacubitril. Echocardiographic and [18F]fluorodeoxyglucose positron emission tomographic imaging revealed that valsartan in the presence or absence of sacubitril reverses the anatomical and metabolic remodeling induced by chronic oxidative stress. Markers of oxidative stress, mitochondrial function, and apoptosis, as well as classical heart failure biomarkers, also normalized following drug treatments despite the persistence of cardiac fibrosis. These findings provide evidence that chemogenetic heart failure is rapidly reversible by drug treatment, setting the stage for the study of novel heart failure therapeutics in this model. The ability of ANG II blockade and neprilysin inhibition to reverse heart failure induced by chronic oxidative stress identifies a central role for cardiac myocyte angiotensin receptors in the pathobiology of cardiac dysfunction caused by oxidative stress. NEW & NOTEWORTHY The chemogenetic approach allows us to distinguish cardiac myocyte-specific pathology from the pleiotropic changes that are characteristic of other “interventional” animal models of heart failure. These features of the chemogenetic heart failure model facilitate the analysis of drug effects on the progression and regression of ventricular remodeling, fibrosis, and dysfunctional signal transduction. Chemogenetic approaches will be highly informative in the study of the roles of redox stress in heart failure providing an opportunity for the identification of novel therapeutic targets.

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“…NEP is a transmembrane zink‐dependent metallopeptidase and is implicated in the degradation of numerous peptides with varying substrate selectivity 18 . Several potential bioactive signalling pathway candidates have been identified including enkephalins and substance P 19 …”

Section: Discussionmentioning

confidence: 99%

“…NEP is a transmembrane zink-dependent metallopeptidase and is implicated in the degradation of numerous peptides with varying substrate selectivity. 18 Several potential bioactive signalling pathway candidates have been identified including enkephalins and substance P. 19 The primary hypothesis for the mechanism of action of NEPi in HFrEF specifically is to increase endogenous NP levels by blocking their inactivation. 18,20 A modest increase in BNP at short term after therapy initiation has been shown.…”

Section: Mechanism Of Action Of Neprilysin Inhibition As the Novel Therapeutic Approach In Heart Failurementioning

confidence: 99%

Neprilysin inhibition does not alter dynamic of proenkephalin‐A 119‐159 and pro‐substance P in heart failure

et al. 2021

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Aims As NEP degrades many substrates, the specific therapeutic mechanism of NEP inhibition with angiotensin receptor neprilysin inhibitor (ARNi) in heart failure with reduced ejection fraction (HFrEF) is not entirely evident. The aim of this study was to investigate the response of two substrates of NEP-the tachykinin and enkephalin systems-to the initiation of ARNi therapy in HFrEF. Methods and results Between 2016 and 2018, 141 consecutive patients with stable HFrEF [74 with initiation of ARNi and 67 controls on continuous angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy] were prospectively enrolled. Plasma proenkephalin-A 119-159 (PENK) and pro-substance P (pro-SP) were serially determined.

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Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure

Cited by 13 publications

References 174 publications

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Reversal of heart failure in a chemogenetic model of persistent cardiac redox stress

Neprilysin inhibition does not alter dynamic of proenkephalin‐A 119‐159 and pro‐substance P in heart failure

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