The present study investigated whether functional, molecular, and biochemical alterations occurring in chronic
heart failure can already be detected in compensated hypertensive
cardiac hypertrophy. Force of contraction (isolated papillary muscle strip preparations), sarcoplasmic reticulum (SR)
protein and
myosin heavy chain isoform expression (Northern and Western blot analysis), myocardial
fibrosis (
collagen stains,
hydroxyproline quantification), myocardial
renin mRNA (RT-PCR), and
angiotensin II levels and plasma
aldosterone concentrations (radioimmunoassay) were studied in hypertrophied myocardium from transgenic rats harboring the mouse Ren-2d gene. Contraction and relaxation velocities of isolated papillary muscle strips were significantly reduced in
cardiac hypertrophy. The beta-/
alpha-myosin heavy chain ratio was significantly increased in the hypertrophied left ventricles, whereas SR Ca2+-
ATPase (SERCA 2a) and
phospholamban mRNA and
protein levels were significantly decreased. The decrease in SERCA 2a was more pronounced than the decrease in
phospholamban levels. There was no increased myocardial
fibrosis. Left ventricular myocardial
renin mRNA and
angiotensin II concentrations, as well as plasma
aldosterone levels, were higher in transgenic than in control rats. In hypertensive
cardiac hypertrophy,
myosin heavy chain isoform shift and reduction of SR
protein levels are related to systolic and diastolic dysfunction, respectively. These alterations precede the development of myocardial
fibrosis. Increased myocardial
renin mRNA and
angiotensin II concentrations suggest that an activated tissue renin-angiotensin system might contribute to these alterations. Since the alterations in compensated
cardiac hypertrophy apparently precede those in chronic
heart failure, they might accelerate the transition from
hypertrophy to failure and could therefore be targets for pharmacological interventions.