Effects of pravastatin on cardiomyocyte hypertrophy and ventricular vulnerability in normolipidemic rats after myocardial infarction.

Reactive cardiomyocyte hypertrophy after myocardial infarction (MI) is an important risk factor for arrhythmias. Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after MI and whether the attenuated hypertrophic effect was via reduced regional ET-1 expression. After ligation of the anterior descending artery, male Wistar rats were randomized to either vehicle, pravastatin, mevalonate, or a combination of the two drugs for 4 weeks. Sham operation served as controls. Pravastatin decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone. The myocardial ET-1 levels at the border zone were 6.3-fold higher (P < 0.0001) in the vehicle group compared with sham group. The increased regional ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the localization of ET-1 mainly in the cardiomyocytes. This was paralleled by a 9.8 +/- 2.3-fold upregulation of preproET-1 mRNA assessed by real-time quantitative reverse transcription-polymerase chain reaction in the vehicle-treated rats, which reduced after administering pravastatin. Cardiomyocyte sizes at the border zone correlated positively with regional ET-1 levels (P = 0.001). Arrhythmic scores during programmed stimulation were significantly higher in the vehicle group than in the pravastatin-treated group (3.0 +/- 1.3 vs. 1.3 +/- 1.0, P < 0.0001). In contrast, pravastatin-induced effects were reversed by the addition of mevalonate, implicating 3-hydroxy-3-methyglutaryl-CoA reductase as the relevant target. The results of the present study suggest that the pravastatin administration after infarction can reduce the inducibility of ventricular arrhythmias as a result of attenuated cardiomyocyte hypertrophy probably through decreased tissue ET-1 level, which is linked to mevalonate metabolism.