The mechanism(s) which contribute to the transition from compensated cardiac hypertrophy to heart failure have remained obscure. Our purpose was to determine whether some of the changes observed during the transition to heart failure might be regulated at the level of gene expression. The spontaneously hypertensive rat (SHR) served as a model for these studies. This model has recently been characterized in terms of functional and morphological features. At 18 mo of age some SHR rats develop clinical signs and symptoms of failure. By combining daily inspections with post-mortem morphological and pathological data, the SHR rats can be divided into those exhibiting failure and those in whom cardiac function is well compensated. Since the failing heart is characterized by impaired function and increased fibrosis, we studied levels of contractile protein and connective tissue mRNA. Total RNA was isolated from hearts of 18-24 mo normotensive Wistar-Kyoto (WKY), spontaneously hypertensive (SHR) rats with (F) and without (NF) evidence of heart failure. Relative mRNA levels for atrial natriuretic factor (ANF), fibronectin (Fn), alpha-skeletal (Sk) and alpha-cardiac (Ca) actin, and alpha- and beta-myosin heavy chain (MHC) were assessed. The transition from compensated hypertrophy to failure was accompanied by decreased contractile protein gene expression (alpha-MHC; 28% of SHR-NF value) and increased expression of fibronectin (301% of SHR-NF value). Expression of ANF was maintained at an elevated level compared to that of age-matched WKY (365%). The results suggest that the impaired function and increased fibrosis observed in failing hearts may be regulated, in part, at the level of gene expression.
