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Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels
AIMS: Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch‐induced circulating biomarkers for predicting hypertension‐associated HF. METHODS AND RESULTS: Circulating levels of 149 proteins were measured by proximity extension a...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373917/ https://www.ncbi.nlm.nih.gov/pubmed/32410391 http://dx.doi.org/10.1002/ehf2.12757 |
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author | Fernandez, Celine Rysä, Jaana Ström, Kristoffer Nilsson, Jan Engström, Gunnar Orho‐Melander, Marju Ruskoaho, Heikki Melander, Olle |
author_facet | Fernandez, Celine Rysä, Jaana Ström, Kristoffer Nilsson, Jan Engström, Gunnar Orho‐Melander, Marju Ruskoaho, Heikki Melander, Olle |
author_sort | Fernandez, Celine |
collection | PubMed |
description | AIMS: Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch‐induced circulating biomarkers for predicting hypertension‐associated HF. METHODS AND RESULTS: Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4742 individuals from the Malmö Diet and Cancer study. Protein levels were compared with stretch‐activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVMs) in response to 1–48 h of mechanical stretch. We also studied the association between protein levels and hypertension and HF incidence using respectively binary logistic and Cox regressions. Levels of 35 proteins were differentially expressed after Bonferroni correction in incident HF vs. control (P < 3.4E−4). Growth differentiation factor‐15 (GDF‐15), interleukin‐6 (IL‐6), IL‐1 receptor type 1, and urokinase plasminogen activator surface receptor had corresponding mRNA levels up‐regulated by stretch in NRVMs at all time points (P < 0.05). These four proteins were individually associated with increased risk of HF after age and sex adjustment [hazard ratio (HR) per standard deviation: 1.19 ≤ HR ≤ 1.49, P ≤ 4.90E−3]. GDF‐15 and IL‐6 were associated with HF independently of each other (1.22 ≤ HR ≤ 1.33, P ≤ 0.001). In subjects with hypertension, these associations remained significant after further adjustment for N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels (1.23 ≤ HR ≤ 1.45, P ≤ 0.001). A higher fasting value of a GDF‐15, IL‐6 score aggregate was associated with increased risk of hypertensive HF after adjustment for all traditional risk factors for HF and NT‐proBNP (HR = 1.31, P = 2.19E−4). CONCLUSIONS: Cardiomyocyte mRNA levels of GDF‐15 and IL‐6 are consistently up‐regulated by stretch, and their circulating protein levels predict HF in hypertensive subjects independently of NT‐proBNP during long‐term follow‐up. Our results encourage further studies on lower blood pressure goals in hypertensive subjects with high GDF‐15 and IL‐6, and interventions targeted at stretch‐induced cardiomyocyte expressed biomarkers. |
format | Online Article Text |
id | pubmed-7373917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73739172020-07-22 Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels Fernandez, Celine Rysä, Jaana Ström, Kristoffer Nilsson, Jan Engström, Gunnar Orho‐Melander, Marju Ruskoaho, Heikki Melander, Olle ESC Heart Fail Original Research Articles AIMS: Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch‐induced circulating biomarkers for predicting hypertension‐associated HF. METHODS AND RESULTS: Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4742 individuals from the Malmö Diet and Cancer study. Protein levels were compared with stretch‐activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVMs) in response to 1–48 h of mechanical stretch. We also studied the association between protein levels and hypertension and HF incidence using respectively binary logistic and Cox regressions. Levels of 35 proteins were differentially expressed after Bonferroni correction in incident HF vs. control (P < 3.4E−4). Growth differentiation factor‐15 (GDF‐15), interleukin‐6 (IL‐6), IL‐1 receptor type 1, and urokinase plasminogen activator surface receptor had corresponding mRNA levels up‐regulated by stretch in NRVMs at all time points (P < 0.05). These four proteins were individually associated with increased risk of HF after age and sex adjustment [hazard ratio (HR) per standard deviation: 1.19 ≤ HR ≤ 1.49, P ≤ 4.90E−3]. GDF‐15 and IL‐6 were associated with HF independently of each other (1.22 ≤ HR ≤ 1.33, P ≤ 0.001). In subjects with hypertension, these associations remained significant after further adjustment for N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels (1.23 ≤ HR ≤ 1.45, P ≤ 0.001). A higher fasting value of a GDF‐15, IL‐6 score aggregate was associated with increased risk of hypertensive HF after adjustment for all traditional risk factors for HF and NT‐proBNP (HR = 1.31, P = 2.19E−4). CONCLUSIONS: Cardiomyocyte mRNA levels of GDF‐15 and IL‐6 are consistently up‐regulated by stretch, and their circulating protein levels predict HF in hypertensive subjects independently of NT‐proBNP during long‐term follow‐up. Our results encourage further studies on lower blood pressure goals in hypertensive subjects with high GDF‐15 and IL‐6, and interventions targeted at stretch‐induced cardiomyocyte expressed biomarkers. John Wiley and Sons Inc. 2020-05-14 /pmc/articles/PMC7373917/ /pubmed/32410391 http://dx.doi.org/10.1002/ehf2.12757 Text en © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research Articles Fernandez, Celine Rysä, Jaana Ström, Kristoffer Nilsson, Jan Engström, Gunnar Orho‐Melander, Marju Ruskoaho, Heikki Melander, Olle Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels |
title | Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels |
title_full | Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels |
title_fullStr | Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels |
title_full_unstemmed | Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels |
title_short | Circulating protein biomarkers predict incident hypertensive heart failure independently of N‐terminal pro‐B‐type natriuretic peptide levels |
title_sort | circulating protein biomarkers predict incident hypertensive heart failure independently of n‐terminal pro‐b‐type natriuretic peptide levels |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373917/ https://www.ncbi.nlm.nih.gov/pubmed/32410391 http://dx.doi.org/10.1002/ehf2.12757 |
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