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Age-related atrial fibrosis

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Abstract

Many age-related diseases are associated with, and may be promoted by, cardiac fibrosis. Transforming growth factor (TGF)-β, hypoxia-induced factor (HIF), and the matrix metalloproteinase (MMP) system have been implicated in fibrogenesis. Thus, we investigated whether age is related to these systems and to atrial fibrosis. Right atrial appendages (RAA) obtained during heart surgery (n = 115) were grouped according to patients’ age (<50 years, 51–60 years, 61–70 years, or >70 years). Echocardiographic ejection fractions (EF) and fibrosis using Sirius-red-stained histological sections were determined. TGF-β was determined by quantitative RT-PCR and hypoxia-related factors [HIF1α, the vascular endothelial growth factor (VEGF)-receptor, CD34 (a surrogate marker for microvessel density), the factor inhibiting HIF (FIH), and prolyl hydroxylase 3 (PHD 3)] were detected by immunostaining. MMP-2 and -9 activity were determined zymographically, and mRNA levels of their common tissue inhibitor TIMP-1 were determined by RT-PCR. Younger patients (<50 years) had significantly less fibrosis (10.1% ± 4.4% vs 16.6% ± 8.3%) than older individuals (>70 years). While HIF1α, FIH, the VEGF-receptor, and CD34 were significantly elevated in the young, TGF-β and PHD3 were suppressed in these patients. MMP-2 and -9 activity was found to be higher while TIMP-1 levels were lower in older patients. Statistical analysis proved age to be the only factor influencing fibrogenesis. With increasing age, RAAs develop significantly more fibrosis. An increase of fibrotic and decrease of hypoxic signalling and microvessel density, coupled with differential expression of MMPs and TIMP-1 favouring fibrosis may have helped promote atrial fibrogenesis.

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Abbreviations

ACE:

Angiotensin converting enzyme

CABG:

Coronary artery bypass graft

EF:

Ejection fraction

FIH:

Factor inhibiting HIF

HIF:

Hypoxia induced factor

HRE:

Hypoxia response elements

IHC:

Immunohistochemistry

KDR:

Kinase insert-domain containing receptor (= VEGF-receptor)

LA:

Left atrium

LV:

Left ventricle

MMP:

Matrix-metalloproteinases

MVD:

Microvessel density

PHD3:

Prolyl hydroxylases 3

RA:

Right atrium

RAA:

Right atrial appendage

RV:

Right ventricle

TGF-β:

Transforming growth factor-β

TIMP:

Tissue inhibitors of metalloproteinases

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Department of Cardiology & Vascular Medicine, II. Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg-Universität, Langenbeckstrasse 1, 55131, Mainz, Germany

    Felix Gramley, Christian Weiss & Thomas Münzel

  2. Department of Cardiology, Pulmonology & Vascular Medicine, RWTH Aachen University, Aachen, Germany

    Felix Gramley, Christian Knackstedt, Obaida R. Rana, Erol Saygili, Dirk Frechen & Patrick Schauerte

  3. Institute for Pathology, Klinikum Dortmund, Dortmund, Germany

    Johann Lorenzen

  4. Institute for Medical Statistics, RWTH Aachen University, Aachen, Germany

    Sven Stanzel

  5. Nuffield Department of Clinical Laboratory Sciences, Oxford University, Oxford, UK

    Francesco Pezzella

  6. Department for Plastic and Hand Surgery, University of Heidelberg, Heidelberg, Germany

    Eva Koellensperger

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  1. Felix Gramley
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  2. Johann Lorenzen
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  3. Christian Knackstedt
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  4. Obaida R. Rana
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  8. Francesco Pezzella
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  9. Eva Koellensperger
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  10. Christian Weiss
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  11. Thomas Münzel
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  12. Patrick Schauerte
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Correspondence to Felix Gramley.

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Gramley, F., Lorenzen, J., Knackstedt, C. et al. Age-related atrial fibrosis. AGE 31, 27–38 (2009). https://doi.org/10.1007/s11357-008-9077-9

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