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Original research
Exploration of pathophysiological pathways for incident atrial fibrillation using a multiplex proteomic chip
  1. John Molvin1,2,
  2. Amra Jujic1,2,
  3. Olle Melander1,3,
  4. Manan Pareek4,5,
  5. Lennart Råstam1,
  6. Ulf Lindblad6,
  7. Bledar Daka6,
  8. Margret Leosdottir1,2,
  9. Peter Nilsson1,3,
  10. Michael Olsen7 and
  11. Martin Magnusson1,2,8
  1. 1Department of Clinical Sciences, Lund University, Clinical Research Center, Malmö, Sweden
  2. 2Department of Cardiology, Skånes universitetssjukhus Malmö, Malmö, Sweden
  3. 3Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
  4. 4Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
  5. 5Department of Cardiology, North Zealand Hospital, Hilleröd, Denmark
  6. 6Department of Public Health and Community Medicine, Sahlgrenska Academy, Goteborg, Sweden
  7. 7Centre for Individualized Medicine in Arterial Diseases, University of Southern Denmark, Odense, Denmark
  8. 8Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
  1. Correspondence to Dr John Molvin; johnmolvin{at}


Objective Atrial fibrillation (AF) is the most common arrhythmia and associated with increased morbidity and mortality. Its increasing prevalence calls for novel biomarkers to identify underlying pathophysiological mechanisms as well as patients at risk.

Methods Plasma samples from 1694 individuals from the Swedish population-based Malmö Preventive Project (mean age 69.5 years; 29.3% female; mean follow-up time 9.7±3.1 years) were analysed with the Olink proximity extension assay CVD III panel consisting of 92 proteins to identify proteins associated with incident AF or atrial flutter, referred to as incident AF. Incident cases of AF (n=278) were retrieved by linkage to the registers. Participants were followed until the first episode of AF or until censoring by death or emigration. Bonferroni-corrected multivariable Cox regression models adjusted for known risk factors were used to explore possible associations of the 92 proteins and incidence of AF.

Results Multivariable Cox regression analyses of 11 proteins associated with incident AF (mean follow-up time 9.7±3.1 years) after Bonferroni correction confirmed N-terminal pro-B-type natriuretic peptide (HR per 1 SD increment (95% CI) 1.80 (1.58 to 2.04); p=1.2×10−19) as risk marker of incident AF. Further, matrix metalloproteinase-2 (1.22 (1.07 to 1.39); p=0.002) and osteopontin (1.27 (1.12 to 1.44); p=2.7×10−4) were associated with incident AF at follow-up independently of traditional risk markers and NT-proBNP.

Conclusion In a general Swedish population, we confirmed the well-known association of NT-proBNP with incident AF and also identified matrix metalloproteinase-2 and osteopontin as novel risk markers for incident AF, independently of traditional risk factors and NT-proBNP.

  • atrial fibrillation
  • matrix metalloproteinase-2
  • NT-proBNP
  • osteopontin

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  • Contributors JM, AJ, OM, MP, LR, UL, BD, ML, PN, MO and MM contributed to study concept and design. JM, ML, MM acquired data. JM, AJ, MP, MO and MM analysed and interpreted data. JM, AJ and MM drafted the manuscript. JM, AJ, OM, MP, LR, UL, BD, ML, PN, MO and MM critically revised the manuscript for important intellectual content. JM, AJ, MP, ML, MO and MM contributed to statistical analysis. OM, LR, UL, PN, MO and MM obtained funding. PN provided administrative, technical or material support. JM, AJ, MM and PN supervised the study. JM, AJ and MM are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding MM was supported by grants from the Wallenberg Centre for Molecular Medicine, Lund University (ALFSKANE-675271), Medical Faculty of Lund University (ALFSKANE-432021; ALFSKANE-436111), Skåne University Hospital, the Crafoord Foundation, the Ernhold Lundstroms Research Foundation, Region Skåne, the Hulda and Conrad Mossfelt Foundation, the Southwest Skåne's Diabetes Foundation, the Kockska Foundation, the Research Funds of Region Skåne and the Swedish Heart and Lung Foundation (2018-0260).

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval The study was approved by the Regional Ethical Review Board at Lund University, Sweden (LU 244-02) and complied with the Helsinki Declaration.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data may be obtained from a third party and are not publicly available.

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