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Olle Melander

Principal investigator

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Circulating protein biomarkers predict incident hypertensive heart failure independently of N-terminal pro-B-type natriuretic peptide levels

Author

  • Celine Fernandez
  • Jaana Rysä
  • Kristoffer Ström
  • Jan Nilsson
  • Gunnar Engström
  • Marju Orho-Melander
  • Heikki Ruskoaho
  • Olle Melander

Summary, in English

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.

Department/s

  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Immunity and Atherosclerosis
  • EpiHealth: Epidemiology for Health
  • Cardiovascular Research - Epidemiology
  • Diabetes - Cardiovascular Disease

Publishing year

2020-08

Language

English

Pages

1891-1899

Publication/Series

ESC Heart Failure

Volume

7

Issue

4

Document type

Journal article

Publisher

John Wiley and Sons

Topic

  • Cardiac and Cardiovascular Systems
  • Endocrinology and Diabetes

Keywords

  • Cardiomyocyte
  • Heart failure
  • Hypertension
  • Prospective cohort
  • Protein panel

Status

Published

Research group

  • Cardiovascular Research - Hypertension
  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Cardiovascular Research - Epidemiology
  • Diabetes - Cardiovascular Disease

ISBN/ISSN/Other

  • ISSN: 2055-5822