Prognostic utility of novel biomarkers of cardiovascular stress in patients with aortic stenosis undergoing valve replacement
Open accessAbstract
Objective: In heart failure populations without aortic stenosis (AS), the prognostic utility of multiple biomarkers in addition to clinical factors has been demonstrated. We aimed to determine whether multiple biomarkers of cardiovascular stress are associated with mortality in patients with AS undergoing aortic valve replacement (AVR) independent of clinical factors. Methods: From a prospective registry of patients with AS, 345 participants who were referred for and treated with AVR (transcatheter (n=183) or surgical (n=162)) were included. Eight biomarkers were measured on blood samples obtained prior to AVR: growth differentiation factor 15 (GDF15), soluble ST2 (sST2), amino-terminal pro-B-type natriuretic peptide (NTproBNP), galectin-3, high-sensitivity cardiac troponin T, myeloperoxidase, high-sensitivity C reactive protein and monocyte chemotactic protein-1. Biomarkers were evaluated based on median value (high vs low) in a Cox proportional hazards model for all-cause mortality and a parsimonious group of biomarkers selected. Mean follow-up was 1.9±1.2 years; 91 patients died. Results: Three biomarkers (GDF15, sST2 and NTproBNP) were retained in the model. One-year mortality was 5%, 12%, 18% and 33% for patients with 0 (n=79), 1 (n=96), 2 (n=87) and 3 (n=83) biomarkers elevated, respectively (p<0.001). After adjustment for the Society of Thoracic Surgeons (STS) risk score, a greater number of elevated biomarkers was associated with increased mortality (referent: 0 elevated): 1 elevated (HR 1.47, 95% CI 0.60 to 3.63, p=0.40), 2 elevated (HR 2.89, 95% CI 1.24 to 6.74, p=0.014) and 3 elevated (HR 4.59, 95% CI 1.97 to 10.71, p<0.001). Among patients at intermediate or high surgical risk (STS score ≥4), 1-year and 2-year mortality rates were 34% and 43% for patients with three biomarkers elevated versus 4% and 4% for patients with 0 biomarkers elevated. When added to the STS score, the number of biomarkers elevated provided a category-free net reclassification improvement of 64% at 1 year (p<0.001). The association between a greater number of elevated biomarkers and increased mortality after valve replacement was similar in the transcatheter and surgical AVR populations. Conclusions: These findings demonstrate the potential utility of multiple biomarkers to aid in risk stratification of patients with AS. Further studies are needed to evaluate their utility in clinical decision-making in specific AS populations.
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The added value of these emerging blood biomarkers beyond established clinical, echocardiographic, tomographic and blood biomarkers has not yet been shown.
“but their incremental value beyond already established clinical, echocardiographic, tomographic and blood biomarkers is yet to be demonstrated.”
From Calcific aortic stenosis (2016) · cites this paper as [198]
The Results section ('Added prognostic utility of multiple biomarkers'; page unavailable) demonstrates improved risk reclassification when the biomarkers were added to the STS score or a clinical model, so their incremental value beyond clinical measures had been shown. The paper does not demonstrate incremental value beyond the full combination of clinical, echocardiographic, tomographic and established blood biomarkers claimed here. (LLM, conf=0.82)
Experimental — accuracy not yet measuredEmerging blood biomarkers such as high-sensitivity cardiac troponin, GDF-15, soluble IL-1 receptor-like 1/ST2 and microRNAs may help detect subclinical or irreversible myocardial dysfunction.
“Emerging blood biomarkers, such high-sensitivity cardiac troponin194;195, growth/differentiation factor 15, soluble interleukin-1 receptor-like 1 (also called protein ST2) and micro RNAs196–198, might be helpful to detect subclinical and/or irreversible myocardial dysfunction”
From Calcific aortic stenosis (2016) · cites this paper as [198]
The Introduction identifies GDF15, soluble ST2 and high-sensitivity troponin as biomarkers of cardiovascular stress, and the Results (Biomarkers and tissue fibrosis and inflammation; page unavailable) link some of them to myocardial fibrosis or inflammation. The paper does not assess microRNAs or establish that these biomarkers detect subclinical or irreversible myocardial dysfunction; its study concerns patients with aortic stenosis undergoing valve replacement. (LLM, conf=0.84)
Experimental — accuracy not yet measuredElevated 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 [6]
The Results (Individual biomarkers and mortality; page unavailable) identify NTproBNP as having a relationship with mortality. Although the study measured cardiac troponin T and galectin-3, the reported three-biomarker mortality model retained neither; the passages do not establish the claimed mortality association for those two markers. The cohort consisted specifically of patients with severe aortic stenosis undergoing valve replacement, not all individuals with CAVS. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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- Authors
- Lindman, B. R., Breyley, J. G., Schilling, J. D., Vatterott, A. M., Zajarias, A., Maniar, H. S., Damiano, R. J., Moon, M. R., Lawton, J. S., Gage, B. F., Sintek, M. A., Aquino, A., Holley, C. L., Patel, N. M., Lawler, C., Lasala, J. M., & Novak, E.
- Affiliations
- Washington University in St. Louis (US)
- Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA
- Corresponding author
- Lindman, Brian R
- ORCID
- Venue
- Heart
- Publisher
- BMJ
- Published
- 2015-06-02
- Volume
- 101
- Issue
- 17
- Pages
- 1382-1388
- ISSN
- 1355-6037 (ISSN-L)
- 1468-201X
- PMC
- PMC4598053
- OpenAlex
- W2183048501
- Cited by
- 114
- References
- 25
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 2 · 2023: 8 · 2022: 12 · 2021: 9 · 2020: 15 · 2019: 8 · 2018: 20 · 2017: 15 · 2016: 7 · 2015: 4
- FWCI
- 11.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Heart (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Edwards Lifesciences
- Washington University in St. Louis
- AtriCure
- BG Medicine
- National Institutes of Health (KL2TR000450, UL1TR000448)
- National Heart, Lung, and Blood Institute (K08HL114889, KO8 HL09837305, K08HL098373, K23HL116660, T32HL007081)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- aortic stenosis, aortic valve replacement, prognostic factors, all-cause mortality, growth differentiation factor 15, soluble ST2, NT-proBNP, galectin-3, myeloperoxidase, C-reactive protein, MCP-1, transcatheter aortic valve implantation, surgical aortic valve replacement, Society of Thoracic Surgeons risk score, heart failure, heart failure with reduced ejection fraction
- MeSH terms
- Interleukin-1 Receptor-Like 1 Protein, Aged, Aged, 80 and over, Aortic Valve Stenosis, Female, Cardiac Catheterization, Humans, Male, Middle Aged, Peptide Fragments, Predictive Value of Tests, Prospective Studies, Receptors, Cell Surface, Registries, Risk Factors, Severity of Illness Index, Stress, Physiological, Time Factors, Biomarkers, Proportional Hazards Models, Treatment Outcome, Risk Assessment, Heart Valve Prosthesis Implantation, Natriuretic Peptide, Brain, Kaplan-Meier Estimate, Growth Differentiation Factor 15
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