B-Type Natriuretic Peptide Clinical Activation in Aortic Stenosis
Open accessAbstract
Objectives This study was conducted to define the association between serum B-type natriuretic peptide (BNP) activation and survival after the diagnosis of aortic stenosis (AS).Background In AS, the link between BNP levels and clinical outcome is in dispute. Failure to account for the normal shifting of BNP ranges with aging in men and women, not using hard endpoints (survival), and not enrolling large series of patients have contributed to the uncertainty.Methods A program of prospective measurement of BNP levels with Doppler echocardiographic AS assessment during the same episode of care was conducted. BNP ratio (measured BNP/maximal normal BNP value specific to age and sex) >1 defined BNP clinical activation.Results In 1,953 consecutive patients with at least moderate AS (aortic valve area 1.03 ± 0.26 cm(2); mean gradient 36 ± 19 mm Hg), median BNP level was 252 pg/ml (interquartile range: 98 to 592 pg/ml); BNP ratio 2.46 (interquartile range 1.03 to 5.66); ejection fraction (EF) 57% ± 15%, and symptoms present in 60% of patients. After adjustment for all survival determinants, BNP clinical activation (BNP ratio >1) independently predicted mortality after diagnosis (p < 0.0001; hazard ratio [HR]: 1.91; 95% CI: 1.55 to 2.35) and provided incremental power to the survival predictive model (p < 0.0001). Eight-year survival was 62 ± 3% with normal BNP levels, 44 ± 3% with BNP ratio of 1 to 2 (adjusted HR: 1.49; 95% CI: 1.17 to 1.90), 25 ± 4% with BNP ratio of 2 to 3 (adjusted HR: 2.12; 95% CI: 1.63 to 2.75), and 15 ± 2% with BNP ratio of ≥3 (adjusted HR: 2.43; 95% CI: 1.94 to 3.05). This strong link to survival was confirmed in asymptomatic patients with normal EF (adjusted HR: 2.35 [95% CI: 1.57 to 3.56] for BNP clinical activation and 2.10 [95% CI: 1.32 to 3.36] for BNP ratio of 1 to 2, 2.25 [95% CI: 1.31 to 3.87] for BNP ratio of 2 to 3, 3.93 [95% CI: 2.40 to 6.43] for BNP ratio of ≥3). Aortic valve replacement was associated with survival improved by a similarly high margin (p = 0.54) with BNP ratio of <2 (HR: 0.68; 95% CI: 0.52 to 0.89; p = 0.003) or BNP ratio of >2 (HR: 0.56; 95% CI: 0.47 to 0.66; p < 0.0001).Conclusions In this large series of patients with AS, BNP clinical activation was associated with excess long-term mortality incrementally and independently of all baseline characteristics. Higher mortality with higher BNP clinical activation, even in asymptomatic patients, emphasizes the importance of appropriate clinical interpretation of BNP levels in managing patients with AS.
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Elevated levels of brain natriuretic peptide, cardiac troponin, and galectin-3 are correlated with all-cause mortality in individuals with CAVS.
“Previous studies showed that elevated levels of brain natriuretic peptide, cardiac troponin, and galectin-3 are correlated with all-cause mortality in individuals with CAVS.6,7,8,9,10”
From Aortic valve-specific genes dysregulated in calcific aortic valve stenosis as potential biomarkers and therapeutic targets (2025) · cites this paper as [8]
The Results (page not specified in the indexed copy) link elevated BNP to increased overall mortality in patients with moderate or severe aortic stenosis. The cited paper does not provide evidence for the claimed associations with cardiac troponin or galectin-3. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA BNP ratio >1 is a powerful independent predictor of mortality in AS, even in asymptomatic patients.
“A BNP ratio of >1 was found to be a powerful independent predictor of mortality in AS, even in patients with asymptomatic AS187.”
From Calcific aortic stenosis (2016) · cites this paper as [187]
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Nakatsuma, K., Taniguchi, T., Morimoto, T., Shiomi, H., Ando, K., Kanamori, N., Murata, K., Kitai, T., Kawase, Y., Izumi, C., et al. (2018) · Heart · doi:10.1136/heartjnl-2018-313746 · Cited by 64 · see citing works
Multimodality Imaging Strategies for the Assessment of Aortic Stenosis
Dulgheru, R., Pîbarot, P., Sengupta, P. P., Piérard, L., Rosenhek, R., Magné, J., Donal, E., Bernard, A., Fattouch, K., Cosyns, B., et al. (2016) · Circulation Cardiovascular Imaging · doi:10.1161/circimaging.115.004352 · Cited by 69 · see citing works
“(ratio-measured brain natriuretic peptide/normal reference brain natriuretic peptide for age and sex, >2).(55) CMR is not”
BackgroundZhang, B., Xu, H., Zhang, H., Liu, Q., Ye, Y., Hao, J., Zhao, Q., Qi, X., Liu, S., Zhang, E., et al. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2020.02.031 · Cited by 63 · see citing works
Self-citationB-Type Natriuretic Peptides and Cardiac Troponins for Diagnosis and Risk-Stratification of Syncope
de Lavallaz, J. D. F., Badertscher, P., Nestelberger, T., Zimmermann, T., Miró, Ò., Salgado, E., Christ, M., Geigy, N., Cullen, L., Than, M. P., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.038358 · Cited by 57 · see citing works
Timing of intervention in asymptomatic patients with valvular heart disease
Baumgartner, H., Iung, B., & Otto, C. M. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa485 · Cited by 57 · see citing works
“19 23”
Clavel, M.-A. A., Tribouilloy, C. M., Vanoverschelde, J., Pizarro, R., Suri, R. M., Szymanski, C., Lazam, S., OBERTI, P. F., Michelena, H. I., Jaffe, A. S., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.06.047 · Cited by 55 · see citing works
Self-citationThe Task Force for the management of COVID-19 of the European Society of Cardiology, Baigent, C., Windecker, S., Andreini, D., Arbelo, E., Barbato, E., Bartorelli, A. L., Baumbach, A., Behr, E. R., Berti, S. L., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab343 · Cited by 53 · see citing works
Elevated Plasma Soluble ST2 Is Associated with Heart Failure Symptoms and Outcome in Aortic Stenosis
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“Although adjusted for age and sex, BNP ratio [20, 21] did not improve the predictive accuracy of BNP.”
BackgroundMethodO'Neill, B. P., Guerrero, M. E., Thourani, V. H., Kodali, S., Heldman, A. W., Williams, M. R., Xu, K., Pichard, A. D., Mack, M. J., Babaliaros, V. C., et al. (2015) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2015.01.561 · Cited by 49 · see citing works
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“predict events in asymptomatic AS (25,26) but may lack specificity.”
BackgroundNatriuretic Peptides for Risk Stratification of Patients With Valvular Aortic Stenosis
Parikh, V. Y., Kim, C., Siegel, R. J., Arsanjani, R., & Rader, F. (2015) · Circulation Heart Failure · doi:10.1161/circheartfailure.114.001649 · Cited by 46 · see citing works
“As established in a large population sample,(7) BNP levels increase with aging, which is why some studies use a BNP ratio (ie, BNP levels adjusted for age-specific normal values).(8) The purpose of this review is to present the data that have emerged during the past 10 years about the usefulness of natriuretic peptide…”
MethodMoura, B., Aimo, A., Al‐Mohammad, A., Flammer, A. J., Barberis, V. I., Bayés‐Genís, A., Rocca, H. B., Fontes‐Carvalho, R., Grapsa, J., Hülsmann, M., et al. (2021) · European Journal of Heart Failure · doi:10.1002/ejhf.2339 · Cited by 44 · see citing works
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Guía ESC/EACTS 2021 sobre el diagnóstico y tratamiento de las valvulopatías
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Plasma biomarkers associated with adverse outcomes in patients with calcific aortic stenosis
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“4%) 0 Postprocedural aortic valve gradient (mmHG) 5 (1-9) 5 (2-9) 4.”
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Self-citationGoodman, A., Kusunose, K., Popović, Z., Parikh, R., Barr, T., Sabik, J. F., Rodriguez, L. L., Svensson, L. G., Griffin, B. P., & Desai, M. Y. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002561 · Cited by 33 · see citing works
“DOI: 10.1161/JAHA.115.002561 Journal of the American Heart Association 9 BNP and Strain in Aortic Stenosis Goodman et al O R IG IN A L R E S E A R C H A previous report has suggested the use of different thresholds, based on age and sex.31 A recent report utilized BNP ratios generated based on these thresholds and dem…”
MethodInfluentialO’Leary, J., Clavel, M.-A. A., Chen, S., Goel, K., O'Neill, B. P., Elmariah, S., Crowley, A., Alu, M. C., Thourani, V. H., Leon, M. B., et al. (2020) · JAMA Cardiology · doi:10.1001/jamacardio.2020.2614 · Cited by 32 · see citing works
Self-citationBiomarkers in Aortic Stenosis: A Systematic Review
Redfors, B., Furer, A., Lindman, B. R., Burkhoff, D., Marquis‐Gravel, G., Francese, D. P., Ben‐Yehuda, O., Pîbarot, P., Gillam, L. D., Leon, M. B., et al. (2017) · Structural Heart · doi:10.1080/24748706.2017.1329959 · Cited by 30 · see citing works
“A recent study showed that BNP activation, defined as the ratio between the measured BNP and the maximum expected BNP for a subject’s age and sex, was a strong and persistent predictor of mortality.(55) The predictive value of BNP may be lower in the elderly, the patient group most commonly affected by AS.”
BackgroundModels and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview
Bogdanova, M., Zabirnyk, A., Malashicheva, A., Semenova, D., Kvitting, J. E., Kaljusto, M., Perez, M. D. M., Kostareva, A. A., Stensløkken, K., Sullivan, G. J., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.835825 · Cited by 30 · see citing works
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Role of advanced left ventricular imaging in adults with aortic stenosis
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Catheter-Based Interventions for the Management of Valvular Heart Disease During Pregnancy
Elkayam, U., Bansal, P., & Mehra, A. (2022) · JACC Advances · doi:10.1016/j.jacadv.2022.100022 · Cited by 26 · see citing works
The ‘wait for symptoms’ strategy in asymptomatic severe aortic stenosis
Román, J. A. S., Vilacosta, I., Antunes, M. J., Iung, B., López, J., & Schäfers, H. (2020) · Heart · doi:10.1136/heartjnl-2020-317323 · Cited by 26 · see citing works
Timing of Intervention in Asymptomatic Patients with Aortic Stenosis
Sevilla, T., Revilla, A., & Román, J. A. S. (2021) · European Cardiology Review · doi:10.15420/ecr.2021.11 · Cited by 21 · see citing works
Ratio of Acceleration Time to Ejection Time for Assessing Aortic Stenosis Severity
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“Several studies have demonstrated that plasma levels of natriuretic peptides are related to symptomatic status,(32) disease severity, and prognosis.(35,36) In our study, patients with AT/ET >0.”
BackgroundLindman, B. R., Pîbarot, P., Schwartz, A. J., Oldemeyer, J. B., Su, Y. R., Goel, K., Cohen, D. J., Fearon, W. F., Babaliaros, V. C., Daniels, D. V., et al. (2025) · Circulation · doi:10.1161/circulationaha.125.074425 · Cited by 24 · see citing works
“6–10 These studies provide the rationale for the guideline recommendation that AVR is reasonable in patients with asymptomatic severe AS and elevated BNP (brain natriuretic peptide) to unload the heart to potentially prevent irreversible cardiac damage and its consequences.”
Duello, K. M., Nagel, J. P., Thomas, C. S., Blackshear, J. L., & Freeman, W. D. (2015) · Neurocritical Care · doi:10.1007/s12028-014-0105-6 · Cited by 23 · see citing works
The left ventricle in aortic stenosis – imaging assessment and clinical implications
Călin, A., Roşca, M., Beladan, C. C., Enache, R., Mateescu, A. D., Ginghină, C., & Popescu, B. A. (2015) · Cardiovascular Ultrasound · doi:10.1186/s12947-015-0017-4 · Cited by 23 · see citing works
“A serum BNP level higher than the normal upper limit for each individual patient (defined as BNP clinical activation) was a powerful predictor of long-term mortality, incrementally and independently of all baseline characteristics in a large cohort of patients with moderate and severe AS [74].”
BackgroundSeoudy, H., Frank, J., Neu, M., Güßefeld, N., Klaus, Y., Freitag‐Wolf, S., Lambers, M., Lutter, G., Dempfle, A., Rangrez, A. Y., et al. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.118.010876 · Cited by 23 · see citing works
“25 BNP is recognized in the current European Society of Cardiology and European Association for Cardio-Thoracic Surgery guidelines for the management of valvular heart disease 2 as the only biomarker with prognostic value in AS.”
Onishi, H., Naganuma, T., Izumo, M., Ouchi, T., Yuki, H., Mitomo, S., & Nakamura, S. (2022) · ESC Heart Failure · doi:10.1002/ehf2.13946 · Cited by 20 · see citing works
Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis
Shah, S. M., Shah, J., Lakey, S., Garg, P., & Ripley, D. P. (2023) · Open Heart · doi:10.1136/openhrt-2022-002244 · Cited by 27 · see citing works
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Targeting vasoactive peptides for managing calcific aortic valve disease
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“In a recent study, BNP clinical activation was detected as a predictor of long-term mortality in patients with moderate or severe AS (92), whereas in a large prospective cohort NT-proBNP had a poor diagnostic value for severe symptomatic AS in elderly patients (91).”
BackgroundTranscatheter Aortic Valve Replacement for Patients with Heart Failure
Himbert, D., & Vahanian, A. S. (2015) · Heart Failure Clinics · doi:10.1016/j.hfc.2014.12.003 · Cited by 21 · see citing works
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Aortic Valve Disease, Transcatheter Aortic Valve Replacement, and the Heart Failure Patient
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The role of cardiac biochemical markers in aortic stenosis
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“association between BNP/NT-proBNP and adverse cardiovascular outcomes (Clavel et al., 2014; Lancellotti et al., 2010b; Monin et al., 2009) others have questioned their prognostic value (Ben-Dor et al.”
BackgroundInfluentialMaeder, M. T., Weber, L., Ammann, P., Buser, M., Ehl, N. F., Gerhard, M., Brenner, R., Haager, P. K., Maisano, F., & Rickli, H. (2020) · ESC Heart Failure · doi:10.1002/ehf2.12614 · Cited by 20 · see citing works
Serum biomarkers in valvular heart disease
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Blood, tissue and imaging biomarkers in calcific aortic valve stenosis
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Vale, N. C., Teles, R. C., Madeira, S., Brito, J., Almeida, M., Nolasco, T., Abecasis, J., Rodrigues, G., Carmo, J., Furstenau, M. D. C., et al. (2018) · Revista Portuguesa de Cardiologia · doi:10.1016/j.repc.2017.06.016 · Cited by 18 · see citing works
“Patients with severe aortic valve stenosis have elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, due to increased myocardial wall stress and pressure overload.(3) Increased concentrations of this peptide have prognostic value in multiple heart conditions, and can be used for risk stratification.”
BackgroundPedersen, A. L. D., Povlsen, J. A., Dybro, A. M., Clemmensen, T. S., Larsen, A. H., Ladefoged, B. T., & Poulsen, S. H. (2020) · Journal of the American Society of Echocardiography · doi:10.1016/j.echo.2020.07.013 · Cited by 17 · see citing works
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Blood biomarkers in left-sided valvular heart disease
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Self-citationBiomarkers Associated with Mortality in Aortic Stenosis: A Systematic Review and Meta-Analysis
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Unique Aspects of Women's Valvular Heart Diseases: Impact for Diagnosis and Treatment
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“26 Serial BNP assessments (every 6 or 12 months) can also be very useful, as they avoid the limitation of mandatory use of the expected value, by using patient ’ s baseline values as a control.”
MethodSelf-citationHadziselimovic, E., Greve, A. M., Sajadieh, A., Olsen, M. H., Kesäniemi, Y. A., Nienaber, C. A., Ray, S. G., Rossebø, A. B., Willenheimer, R. B., Wachtell, K., et al. (2022) · JAMA Cardiology · doi:10.1001/jamacardio.2021.5916 · Cited by 14 · see citing works
YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis
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Assessment of Cardiac Damage in Aortic Stenosis
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“severity, left ventricular (LV) remodeling, and prognosis in severe aortic stenosis (AS).(1,2) While studies have shown the prognostic util-”
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Aortic stenosis in patients with kidney failure: Is there an advantage for a PD-first policy ?
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Factors associated with the progression of aortic valve calcification in older adults
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Multi-biomarker mortality prediction in patients with aortic stenosis undergoing valve replacement.
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“This has stimulated interest in circulating biomarkers as more objective markers of disease progression (13,14), but definitive studies are lacking.”
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Great debate: all patients with asymptomatic severe aortic stenosis need valve replacement
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The Role of Extravalvular Cardiac Damage Staging in Aortic Valve Disease Management
Tastet, L. L., Généreux, P., Bernard, J., & Pîbarot, P. (2021) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2021.01.020 · Cited by 11 · see citing works
Perry, A., Stein, E. J., Biersmith, M. A., Fearon, W. F., Elmariah, S., Kim, J. B., Clark, D. E., Patel, J. N., Gonzales, H. M., Baker, M., et al. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.122.026529 · Cited by 11 · see citing works
Severe aortic valve stenosis: Symptoms, biochemical markers, and global longitudinal strain
Zappulla, P., Bottaro, G., Deste, W., Famà, F., Agnello, F. G., Trovato, D., Indelicato, A., Barbanti, M., Sgroi, C., Monte, I. P., et al. (2020) · Journal of Cardiovascular Echography · doi:10.4103/jcecho.jcecho_13_20 · Cited by 10 · see citing works
“Different studies[11,24-28] have presented the relation between B-type natriuretic peptide and the amount of LV fibrosis and myocardial dysfunction.”
BackgroundWatchful waiting care or early intervention in asymptomatic severe aortic stenosis: Where we are
Ennezat, P. V., Malergue, M., Jemtel, T. H. L., & Abergel, É. (2020) · Archives of cardiovascular diseases · doi:10.1016/j.acvd.2020.07.002 · Cited by 10 · see citing works
Prognostic Value of Lung Ultrasound in Aortic Stenosis
Szabó, I. A., Gargani, L., Morvai-Illés, B., Polestyuk-Németh, N., Frigy, A., Varga, A., & Ágoston, G. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.838479 · Cited by 10 · see citing works
Multiple biomarker panel to screen for severe aortic stenosis: results from the CASABLANCA study
Elmariah, S., McCarthy, C. P., Ibrahim, N. E., Furman, D., Mukai, R., Magaret, C. A., Rhyne, R. F., Barnes, G., van Kimmenade, R. R. J., & Januzzi, J. L. (2018) · Open Heart · doi:10.1136/openhrt-2018-000916 · Cited by 10 · see citing works
- Authors
- Clavel, M.-A., Malouf, J., Michelena, H. I., Suri, R. M., Jaffe, A. S., Mahoney, D. W., & Enriquez-Sarano, M.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Enriquez-Sarano, Maurice
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 63
- Issue
- 19
- Pages
- 2016-2025
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W56250199
- Cited by
- 226
- References
- 48
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 10 · 2023: 20 · 2022: 19 · 2021: 16 · 2020: 29 · 2019: 19 · 2018: 17 · 2017: 24 · 2016: 17 · 2015: 15 · 2014: 5 · 2013: 1
- FWCI
- 13.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Corpus Université Laval (Université Laval) (submittedVersion)
- Funders
- Canadian Institute of Health Research
- Abbott Diagnostics
- Edwards Lifesciences
- St. Jude Medical
- Sorin Group
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- brain natriuretic peptide, aortic stenosis, mortality prediction, survival after diagnosis, asymptomatic aortic stenosis, ejection fraction, Doppler echocardiography, prognostic factors, heart failure risk stratification, heart failure hospitalization, heart failure mortality, heart failure readmission
- MeSH terms
- Aged, Aged, 80 and over, Aortic Valve Stenosis, Female, Follow-Up Studies, Humans, Male, Middle Aged, Pilot Projects, Prospective Studies, Time Factors, Cohort Studies, Biomarkers, Survival Rate, Natriuretic Peptide, Brain
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