Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure

Objective Extracellular matrix, particularly type I fibrillar collagen, pro vides tensile strength that allows cardiac muscle to perform systolic and d iastolic functions. Collagen is induced during the transition from compensa tory hypertrophy to heart failure. We hypothesized that cardiac stiffness d uring decompensatory hypertrophy is partly due to a decreased elastin:colla gen ratio. Materials and methods We prepared left ventricular tissue homogenates from spontaneously hypertensive rats (SHR) aged 30-36 weeks, which had compensat ory hypertrophy with no heart failure, and from SHR aged 70-92 weeks, which had decompensatory hypertrophy with heart failure. Age- and sex-matched Wi star-Kyoto (WKY) rats were used as normotensive controls. In both SHR group s, increased levels of collagen were detected by immune-blot analysis using type I collagen antibody. Elastin and collagen were quantitated by measuri ng desmosine/isodesmosine and hydroxyproline spectrophometrically, respecti vely. To determine whether the decrease in elastin content was due to incre ased elastinolytic activity of matrix metalloproteinase-2, we performed gel atin and elastin zymography on left ventricular tissue homogenates from con trol rats, SHR with compensatory hypertrophy and SHR with heart failure. Results The elastin : collagen ratio was 0.242 +/- 0.008 in hearts from WKY rats. In SHR without heart failure, the ratio was decreased to 0.073 +/- 0 .003 and in decompensatory hypertrophy with heart failure, the ratio decrea sed to 0.012 +/- 0.005. Matrix metalloproteinase-2 activity was increased s ignificantly in SHR with heart failure compared with controls (P < 0.001). The level of tissue inhibitor of metalloproteinase-4 was increased in compe nsatory hypertrophy and markedly reduced in heart failure. Decorin was stro ngly reduced in decompensatory heart failure compared with control hearts. Conclusions Since collagen was induced in SHR with heart failure, decorin a nd elastin were decreased and the ratios of gelatinase A and elastase to ti ssue inhibitor of metalloproteinase-4 were increased, we conclude that hear t failure is associated with adverse extracellular matrix remodeling. (C) L ippincott Williams & Wilkins.