Heart failure is a progressive disease with an extremely poor prognosis. The failing heart is characterized by impaired cardiac muscle function and increased interstitial fibrosis. We have shown that these processes are regulated at least in part at the level of gene expression. During the transition to heart failure, the expression of `-myosin heavy chain is decreased, while that of genes encoding and regulating extracellular matrix proteins is increased. The purposes of this project were to 1) to determin whether chronic inhibition of angiotensin converting enzyme (captopril) initiated in midlife would prevent the alterations in gene expression associated with the transition to failure, and 2) to determine whether captopril treatment after signs of failure were observed would reverse failure-associated changes in gene expression. We studied hearts from 18-2 mo spontaneously hypertensive rats with signs heart failure (SHR-F) or without evidence of failure (SHR-NF), SHRs treated with captopril (2 g/l in drinking water) beginning at 12 mo of age (SHR-Rx12), 18 mo of age (SHR- Rx18) or after signs of failure were detected (SHR-F-Rx) and from age- matched normotensive Wistar-Kyoto (WKY) rats. Among untreated SHRs 56% developed heart failure by 24 mo of age (SHR-F), while none of the SHR-Rx12 or SHR-Rx18 rats exhibited failure. Captopril (Rx12 and Rx18) reversed or prevented 60-70% of the LV hypertrophy observed in SHR rats. While the level of ALPHA-myosin heavy chain (MHC) mRNA was decreased in the LV to 1/3 and 1/5 of the SHR-NF and WKY values, respectively, Rx12 increased alpha-MH mRNA levels 10-fold compared to SHR-F and 2-fold greater than WKY. Levels of atrial natriuretic factor (ANF) mRNA which were elevated 3-fold in the L of SHR-NF rats, and an additional 1.6-fold in SHR-F, were reduced to WKY levels in Rx12. Transforming growth factor-beta1 (TGF-beta1) mRNA abundanc increased 1.3-fold in the LV of SHR-F, but decreased to 1/2 the WKY level i SHR-Rx12 rats. SHR-Rx18 rats exhibited qualitatively similar, but somewhat smaller changes in gene expression. SHR-F-Rx rats exhibited enhanced survival, and compared to SHR-F, complete reversal of changes in TGFbeta1, ANF, `-MHC mRNA levels. Chronic treatment with captropril prevented the transition to failure in SHRs while acute intervention in SHRs with signs o heart failure completely reversed the failure-associated changes in gene expression.
