Toward a New Paradigm for Targeted Natriuretic Peptide Enhancement in Heart Failure
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SUBMITTER: Gidlof O
PROVIDER: S-EPMC8548580 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesThis study was conducted to determine whether urinary excretion of C-type natriuretic peptide (CNP) is elevated in acute decompensated heart failure (ADHF) and whether elevated levels predict adverse outcomes.BackgroundUrinary CNP has been detected in patients with heart failure, but its clinical significance and prognostic utility, compared to established kidney injury biomarkers, in ADHF is unknown.MethodsWe measured 24-h urinary excretion and concurrent plasma concentrations of CNP22, CNP53, and NT-CNP53 in 58 ADHF patients and 20 healthy control subjects. Urinary kidney injury molecule (KIM)-1 and neutrophil gelatinase–associated lipocalin (NGAL) and plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) were also measured. Mortality and all-cause rehospitalization/death were assessed over a follow-up of 1.5 ± 0.9 years.ResultsADHF patients had higher urinary excretion of all 3 CNP molecular forms than did controls. Plasma CNP22 and CNP53 were elevated in ADHF but showed limited correlation with urinary excretion, suggesting that mainly renal-derived CNP appears in urine. Plasma NT-proBNP and urinary KIM-1 were also elevated in ADHF (p < 0.0001); urinary NGAL was similar to that in controls. At 6 months, event-free survival values in ADHF patients were 86% for mortality and 59% for all-cause rehospitalization/death. On Cox regression analysis, urinary NT-CNP53 was the only predictor of mortality (hazard ratio: 1.7; 95% confidence interval: 1.1 to 2.4; p = 0.01) and all-cause rehospitalization/death (hazard ratio: 1.8; 95% confidence interval: 1.3 to 2.4; p = 0.0004), even after adjustment. Integrated discrimination analysis suggested that urinary NT-CNP53 combined with plasma NT-proBNP improved the prediction of adverse outcomes.ConclusionsThe findings from this study support the clinical utility of urinary CNP molecular forms. In ADHF, urinary NT-CNP53 correlated with prognosis, better predicted outcomes than did urinary NGAL and KIM-1, and improved the prognostic value of plasma NT-proBNP.
| S-EPMC3825509 | biostudies-literature
Project description:Heart failure (HF) continues to be a public health burden despite advances in therapy, and the natriuretic peptide (NP) system is clearly of critical importance in this setting, spawning valuable diagnostic and prognostic testing, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), as well as current and future therapeutics, including recombinant natriuretic peptides (e.g., carperitide, nesiritide) and recently sacubitril, which inhibits the key clearance mechanism for NPs. This article intends to summarize the existing evidence for the role of NP system genetic variation on cardiovascular phenotypes relevant to HF with particular focus on the potential impact on pharmacologic therapies.Several genes in NP system have been interrogated, in many cases genetic variation impacting protein quantity and function or related disease states. Recent data supports genetic variants potentially impacting pharmacokinetics or dynamics of medications targeting the pathway. Growing evidence indicates the importance of genetic variation to the functioning of the NP system and its pharmacologic manipulation.
| S-EPMC5681877 | biostudies-literature
Project description: Not available
| S-EPMC5449577 | biostudies-literature
Project description:The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril/valsartan in heart failure (HF) due to the augmentation of the NPS. Here, we will review important insights into the biology of the NPS, the role of precision medicine, and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.
| S-EPMC9897690 | biostudies-literature
Project description:There is increasing interest in the concept of personalised medicine, whereby conditions with common pathophysiologies are targeted together, and also using biomarkers to identify patients who will most benefit from certain interventions. Several data sets indicate that natriuretic peptides are effective in refining risk prediction for heart failure and cardiovascular disease and add predictive power to conventional risk factors. To date two trials have tested the approach of using natriuretic peptides as part of a strategy to identify those at highest risk of cardiovascular events: St. Vincent's Screening to Prevent Heart Failure (STOP-HF) and N-terminal Pro-brain Natriuretic Peptide Guided Primary Prevention of Cardiovascular Events in Diabetic Patients (PONTIAC). These have shown natriuretic peptide-based screening and targeted prevention can reduce heart failure and left ventricular dysfunction and other major cardiovascular events. This approach is now part of North American guidelines.
| S-EPMC5789219 | biostudies-other
Project description:AimsWe have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy.Methods and resultsWe utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (-39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo.ConclusionAmong patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.
| S-EPMC4874857 | biostudies-literature
Project description:Dilated cardiomyopathy is a major cause of heart failure (HF) that affects millions. Corin cleaves and biologically activates pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). High corin levels reduce the development of systolic dysfunction and HF in experimental dilated cardiomyopathy. Yet, patients with significant HF unexpectedly show low corin levels with high plasma ANP/BNP levels. Therefore, we examined the relationship between cardiac corin expression, ANP/BNP levels, and the stages of HF. We used a well-established, dilated cardiomyopathy model to evaluate gene and protein expression as mice longitudinally developed Stages A-D HF. Cardiac systolic function (ejection fraction) continuously declined over time (P<0.001). Cardiac corin transcripts were decreased at early Stage B HF and remained low through Stages C and D (P<0.001). Cardiac corin levels were positively correlated with systolic function (r=0.96, P=0.003) and inversely with lung water (r=-0.92, P=0.001). In contrast, cardiac pro-ANP/BNP transcripts increased later (Stages C and D) and plasma levels rose only with terminal HF (Stage D, P<0.001). Immunoreactive plasma ANP and BNP levels were positively associated with plasma cyclic guanosine monophosphate levels (r=0.82, P=0.01 and r=0.8, P=0.02, respectively). In experimental dilated cardiomyopathy, corin levels declined early with progressive systolic dysfunction before the development of HF, whereas significant increases in plasma ANP, BNP, and cyclic guanosine monophosphate levels were found only in later stage (C and D) HF. This dyssynchrony in expression of corin versus ANP/BNP may impair cleavage activation of pro-natriuretic peptides, and thereby promote the transition from earlier to later stage HF.
| S-EPMC4790413 | biostudies-literature
Project description:BACKGROUND:The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial demonstrated that a strategy to "guide" application of guideline-directed medical therapy (GDMT) by reducing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was not superior to GDMT alone. OBJECTIVES:The purpose of this study was to examine the prognostic meaning of NT-proBNP changes following heart failure (HF) therapy intensification relative to the goal NT-proBNP value of 1,000 pg/ml explored in the GUIDE-IT trial. METHODS:A total of 638 study participants were included who were alive and had available NT-proBNP results 90 days after randomization. Rates of subsequent cardiovascular (CV) death/HF hospitalization or all-cause mortality during follow-up and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall scores were analyzed. RESULTS:A total of 198 (31.0%) subjects had an NT-proBNP ?1,000 pg/ml at 90 days with no difference in achievement of NT-proBNP goal between the biomarker-guided and usual care arms. NT-proBNP ?1,000 pg/ml by 90 days was associated with longer freedom from CV/HF hospitalization or all-cause mortality (p < 0.001 for both) and lower adjusted hazard of subsequent HF hospitalization/CV death (hazard ratio: 0.26; 95% confidence interval: 0.15 to 0.46; p < 0.001) and all-cause mortality (hazard ratio: 0.34; 95% confidence interval: 0.15 to 0.77; p = 0.009). Regardless of elevated baseline concentration, an NT-proBNP ?1,000 pg/ml at 90 days was associated with better outcomes and significantly better KCCQ overall scores (p = 0.02). CONCLUSIONS:Patients with heart failure with reduced ejection fraction whose NT-proBNP levels decreased to ?1,000 pg/ml during GDMT had better outcomes. These findings may help to understand the results of the GUIDE-IT trial. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).
| S-EPMC6719723 | biostudies-literature
Project description:ObjectivesThe purpose of the present study was to translate our laboratory investigations to establish safety and efficacy of 8 weeks of chronic SC B-type natriuretic peptide (BNP) administration in human Stage C heart failure (HF).BackgroundB-Type natriuretic peptide is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin inhibiting, and lusitropic properties. We have previously demonstrated that chronic cardiac hormone replacement with subcutaneous (SC) administration of BNP in experimental HF resulted in improved cardiovascular function.MethodsWe performed a randomized double-blind placebo-controlled proof of concept study comparing 8 weeks of SC BNP (10 μg/kg bid) (n = 20) with placebo (n = 20) in patients with ejection fraction <35% and New York Heart Association functional class II to III HF. Primary outcomes were left ventricular (LV) volumes and LV mass determined by cardiac magnetic resonance imaging. Secondary outcomes include LV filling pressure by Doppler echo, humoral function, and renal function.ResultsEight weeks of chronic SC BNP resulted in a greater reduction of LV systolic and diastolic volume index and LV mass index as compared with placebo. There was a significantly greater improvement of Minnesota Living with Heart Failure score, LV filling pressure as demonstrated by the reductions of E/e' ratio, and decrease in left atrial volume index as compared with placebo. Glomerular filtration rate was preserved with SC BNP, as was the ability to activate plasma 3',5'-cyclic guanosine monophosphate (p < 0.05 vs. placebo).ConclusionsIn this pilot proof of concept study, chronic protein therapy with SC BNP improved LV remodeling, LV filling pressure, and Minnesota Living with Heart Failure score in patients with stable systolic HF on optimal therapy. Renin-angiotensin was suppressed, and glomerular filtration rate was preserved. Subcutaneous BNP represents a novel, safe, and efficacious protein therapeutic strategy in human HF. Further studies are warranted to determine whether these physiologic observations can be translated into improved clinical outcomes and ultimately delay the progression of HF. (Cardiac Hormone Replacement With BNP in Heart Failure: A Novel Therapeutic Strategy; NCT00252187).
| S-EPMC3555560 | biostudies-literature
Project description:Exogenous atrial natriuretic peptide (ANP) may be a logical treatment for heart failure (HF) patients with ANP deficiency. Lower ANP concentrations may result from HF with preserved ejection fraction (HFpEF), which also results in lower brain natriuretic peptide levels in HFpEF relative to HF with reduced ejection fraction (HFrEF), although clinical features regarding circulating ANP in HFpEF and HFrEF have not been fully investigated during acute HF. Here, we characterized the differential regulation of circulating ANP and the efficacy of exogenous ANP (carperitide) in patients with acute HF, especially HFpEF. Serum ANP levels before treatment and the diuretic effect of 0.0125 μg/kg/min of carperitide alone for the first 6 h were prospectively evaluated in 113 patients with acute HF who were divided into two groups: HFpEF vs. HFrEF. We mainly analysed the impact of baseline ANP levels and the presence of HFpEF on the diuretic effect of exogenous ANP. There was an inverse relationship between ANP levels and the diuretic effect of exogenous ANP (r2 = 0.19, P < 0.001). Patients with HFpEF had lower ANP levels (P < 0.001) and a greater diuretic effect of exogenous ANP than patients HFrEF (P < 0.001). HFpEF was an independent predictor of greater diuretic effect of exogenous ANP (P = 0.003), as with a lower baseline ANP level (P = 0.004). Patients with HFpEF might have an aspect of ANP deficiency and represent a promising therapeutic target for modulating circulating ANP.
| S-EPMC7754892 | biostudies-literature