Dataset Information

Active B-Type Natriuretic Peptide Measured by Mass Spectrometry and Response to Sacubitril/Valsartan.

ABSTRACT:

Background

B-type natriuretic peptide (BNP) immunoassays (BNP_ia) do not differentiate active and inactive forms. Inactive NT-proBNP is used to track heart failure (HF) during treatment with sacubitril/valsartan, which inhibits BNP degradation. Mass spectrometry (MS) may better assess effects of HF treatment on biologically active BNP1-32.

Methods and results

We developed a MS assay with immediate protease inhibition to quantify BNP1-32 over a linear range, using labeled recombinant BNP standard. In 4 healthy volunteers, BNP1-32 by MS (BNP_MS) increased from below the 5 pg/mL detection limit to 228 pg/mL after nesiritide. In patients with HF, BNP_MS was measured in parallel with BNP and NT-proBNP immunoassays before and during sacubitril/valsartan treatment. BNP_MS was 4.4-fold lower than BNP_ia in patients with HF. Among patients not taking sacubitril/valsartan and without end-stage renal disease, BNP_MS correlated with BNP_ia (r_s = 0.77, P < .001) and NT-proBNP (r_s = 0.74, P < .001). After a median of 8 weeks on sacubitril/valsartan, active BNP_MS levels decreased by 50% (interquartile range -98.3% to 41.7%, n = 22, P = .048) and correlated with NT-proBNP (r_s = 0.64, P < .001), but not with BNP_ia (r_s = 0.46, P = .057).

Conclusions

Active BNP measured by MS accounts for only a small amount of BNP measured by immunoassays. Although decreased BNP production was anticipated to be masked by inhibition of degradation, levels of active BNP decreased during chronic sacubitril/valsartan treatment.

SUBMITTER: Dillon EM

PROVIDER: S-EPMC8578199 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Active B-Type Natriuretic Peptide Measured by Mass Spectrometry and Response to Sacubitril/Valsartan.

Dillon Erica M EM Wei Shouzuo D SD Gupta Deepak K DK Nian Hui H Rodibaugh Brooks S BS Bachmann Katherine N KN Naftilan Allen J AJ Stevenson Lynne W LW Brown Nancy J NJ

Journal of cardiac failure 20210613 11

<h4>Background</h4>B-type natriuretic peptide (BNP) immunoassays (BNP<sub>ia</sub>) do not differentiate active and inactive forms. Inactive NT-proBNP is used to track heart failure (HF) during treatment with sacubitril/valsartan, which inhibits BNP degradation. Mass spectrometry (MS) may better assess effects of HF treatment on biologically active BNP1-32.<h4>Methods and results</h4>We developed a MS assay with immediate protease inhibition to quantify BNP1-32 over a linear range, using labeled ...[more]

PMID: 34133968

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Project description:BackgroundNatriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended.ObjectivesThe purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan.MethodsBNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF.ResultsMedian BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively).ConclusionsCirculating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).

Project description:BackgroundEarlier studies showed that measured changes in plasma B-type natriuretic peptide (BNP) levels are inconsistent after sacubitril/valsartan administration. The reason remains unknown but may reflect the fact that BNP immunoreactivity measured with commercial BNP assays (BNPcom) includes both mature BNP and proBNP, and neprilysin degrades only mature BNP. In addition, the responsiveness to sacubitril/valsartan varies among patients with heart failure. We investigated the mechanism underlying the inconsistency of BNP measurements after sacubitril/valsartan.MethodsWe measured plasma mature BNP, proBNP and total BNP (mature BNP+proBNP) levels with our immunochemiluminescent assay as well as NT-proBNP, A-type natriuretic peptide (ANP) and BNPcom with conventional assays in 54 patients with heart failure, before (baseline) and after 2, 4, 8 and 12 weeks of sacubitril/valsartan administration. Responders were defined as having NT-proBNP levels at <70% of baseline after 12 weeks.ResultsAmong all patients, total BNP and BNPcom did not change with sacubitril/valsartan treatment, whereas NT-proBNP and proBNP decreased, mature BNP modestly increased and ANP greatly increased. Responders (n=31) exhibited smaller %changes in all natriuretic peptide levels than non-responders (n=23; all p<0.01). Receiver operating characteristic curves analysis to assess the ability of the %change in each natriuretic peptide at 4 weeks to detect responders showed that the area under the curve was about 0.80 for each peptide. There were good correlations between plasma natriuretic peptides levels at baseline and throughout the sacubitril/valsartan administration.ConclusionThese results suggest that the magnitude and direction of change in each BNP form depends on its substrate specificity for neprilysin, that differences in plasma levels of each BNP form between responders and non-responders appear early and persist and that BNPcom levels at 4 weeks can be applicable to prediction of the responders. Notably, our findings show that the idea that BNPcom cannot be used as a marker of heart failure after sacubitril/valsartan should be reconsidered.

Project description:BackgroundThe ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides.MethodsWe examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death.ResultsCompared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45-0.71]; tertile 3, hazard ratio, 0.54 [0.43-0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27-1.51) and 8 months, 1.32 (95% CI, 1.20-1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline (Pinteraction=0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes (Pinteraction ≥0.31).ConclusionsIn patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio.RegistrationURL: https://www.Clinicaltrialsgov; Unique Identifier: NCT01035255.

Project description:ImportanceIn patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain.ObjectiveTo determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function.Design, setting, and participantsProspective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018.ExposuresNT-proBNP concentrations among patients treated with sacubitril-valsartan.Main outcomes and measuresThe primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months.ResultsAmong 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%).Conclusions and relevanceIn this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF.Trial registrationClinicalTrials.gov Identifier: NCT02887183.

Project description:BackgroundThe period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death.ObjectivesThis study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF).MethodsIn this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region.ResultsOf 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (≤30 days), 24.2 (31 to 90 days), 20.7 (91 to 180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31 to 90 days), and 3.4% (91 to 180 days), whereas no risk reduction was observed in patients screened >180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050).ConclusionsRecent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711).

Dataset Information

Active B-Type Natriuretic Peptide Measured by Mass Spectrometry and Response to Sacubitril/Valsartan.

Background

Methods and results

Conclusions

Publications

Active B-Type Natriuretic Peptide Measured by Mass Spectrometry and Response to Sacubitril/Valsartan.

Similar Datasets

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