title: Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure.
abstract: The cardiac extracellular matrix (ECM) maintains the structural and mechanical integrity of the myocardium. We determined the alterations in the composition of the ECM coincident with the transition from compensated left ventricular (LV) hypertrophy (LVH) to symptomatic congestive heart failure (CHF) and the mechanisms underlying such changes. Heart failure was induced in ferrets by aortic banding. Myocardial collagen content was assessed by HPLC and histological analysis. Matrix metalloproteinase (MMP) activity and tissue inhibitor of metalloproteinase (TIMP) expression were evaluated using gelatin zymography and Western blotting, respectively. LV free wall thickness increased by 29% in asymptomatic LVH and was associated with a 20% increase in interstitial fibrosis (P < 0.05). CHF was coincident with increased plasma angiotensin II levels (149 +/- 48, 40 +/- 19, and 5.6 +/- 1 pg/ml for CHF, LVH, and sham, respectively; P < 0.01, CHF vs. sham and LVH), ventricular dilatation (LV internal diameter = 15 +/- 0.4 vs. 9 +/- 0.1 mm, P < 0.05), increased active MMP-9 (3.0- and 2.2-fold increase over sham and LVH, respectively, n = 5-10 animals per group, P < 0.01), and reduced myocardial total collagen content (3.5 +/- 0.4, 2.6 +/- 0.3, and 2.2 +/- 0.3% in sham, LVH, and CHF, respectively, P < 0.05). In CHF the distribution of collagen was markedly altered, becoming punctate in nature. No difference in MMP-2 activity, TIMP-1, TIMP-2, TIMP-3, or TIMP-4 expression, or collagen cross-linking was found at any time. The present work demonstrates structural reorganization and loss of collagen from cardiac ECM during the transition to decompensated CHF. The enhanced MMP-9 activity coincident with the transition to CHF provides potential therapeutic opportunities for managing the progression from asymptomatic LVH to symptomatic CHF.
authors.affiliation: Unit of Cardiac Physiology, Division of Cardiovascular & Endocrine Sciences, Univ of Manchester, 3.08 Core Technology Facility, Manchester, UK.
authors.forename: H K
authors.initials: HK
authors.lastname: Graham
authors.forename: A W
authors.initials: AW
authors.lastname: Trafford
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005289:Ferrets; D006333:Heart Failure / Q000503:physiopathology*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D014664:Vasodilation; D018754:Ventricular Dysfunction / Q000503:physiopathology*
chemical_list: D003094:Collagen