Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure

Statin therapy may be associated with lower mortality in patients with heart failure, but the underlying mechanism of such an association is unknown. We have evaluated the effects of pitavastatin on cardiac function and survival in a rat model of hypertensive heart failure and investigated the molecular mechanism of the observed effects. Dahl salt-sensitive rats fed with high-salt diet from 7 weeks of age developed compensatory left ventricular hypertrophy at 12 weeks and heart failure at 19 weeks. Dahl salt-sensitive rats were treated with either vehicle or pitavastatin (0.3 mg/kg per day) from 7 or 12 weeks. Both early-onset and late-onset pitavastatin treatment reduced left ventricular fibrosis, improved cardiac function, and increased the survival rate apparent at 19 weeks. The increases in the expression levels of hypertrophic, profibrotic, and metalloproteinase genes as well as in gelatinase activities in the heart induced by the high-salt diet were suppressed by pitavastatin treatment. Furthermore, the level of cardiac endothelin-1 was increased in association with the development of heart failure in a manner sensitive to treatment with pitavastatin. Both early and late pitavastatin treatment thus improved cardiac function and survival, with modulation of extracellular matrix remodeling and endothelin-1 signaling possibly contributing to these beneficial effects.