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04 The Cardiac Extracellular Matrix is Remodelled Divergently with Age in Heart Failure: A Role for Altered Collagen Degradation in an Ovine Rapid Pacing Model
  1. MA Horn,
  2. HK Graham,
  3. KM Dibb,
  4. AW Trafford
  1. Unit of Cardiac Physiology, The University of Manchester, Manchester, UK

Abstract

Alterations to the amount, quality and/or distribution of the cardiac extracellular matrix (ECM) are defining features of the structural remodelling which occurs in heart failure (HF). However, whether the ECM remodelling which occurs in the aged failing heart occurs to the same extent as in the young remains to be determined.

HF was instigated in sheep aged either 18 months (young) or >8 years (aged) by rapid ventricular pacing (210 bpm). HF increased LV diameter and reduced fractional shortening (measured by echocardiography) in both young and aged animals (all P<0.001), although these changes were more pronounced in the aged (P<0.05). LV collagen content measured from picro-sirius red-stained LV sections was altered with HF in an age-dependent manner - with collagen accumulation in young HF (P<0.001) and depletion in aged HF (P<0.05). Matrix metalloproteinase-2 (MMP-2) activity determined from gelatin zymograms was enhanced with both ageing and in young HF (both P<0.05). Protein levels of tissue inhibitor of metalloproteinases (TIMPs) 3 & 4 quantified by immunoblotting were reduced in aged HF only (P<0.05). Levels of secreted protein acidic and rich in cysteine (SPARC) were increased in aged hearts compared to young controls (P<0.05) whilst serum procollagen type I C-peptide (PICP) was increased in both young failing (P<0.05) and aged failing (P<0.01) animals, as measured using specific ELISA.

In conclusion, remodelling of the cardiac ECM in HF is age-dependent. Diminished TIMP levels only in aged HF alongside enhanced collagen synthesis in HF provide a potential mechanism for this age-dependent response.

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