Statins reduce low-density lipoprotein cholesterol (LDL-C) and decrease cardiovascular events. Although statins are generally well tolerated, the FDA warns that statins may induce skeletal muscle side effects, cognitive changes and increased fasting glucose levels. Skeletal muscle biopsies from patients with statin myopathy have revealed defects in mitochondrial ultrastructure. Impaired mitochondrial function has been postulated as a key cause of statin-induced myopathy and hepatotoxicity. Long-term statin effects on cardiac muscle are currently unknown.
Wild type mice received atorvastatin, pravastatin or vehicle daily for seven months by oral gavage. Atorvastatin and pravastatin reduced LDL-C compared to vehicle. Echocardiography at two-week intervals showed no differences in %FS, %EF, circumferential fiber shortening and ventricular wall thicknesses between atorvastatin, pravastatin and vehicle treated mice. After seven months of atorvastatin, pravastatin or vehicle administration cardiac muscles (n=21-29) were analyzed, and only atorvastatin treated hearts revealed: A) swollen and misaligned mitochondria and accumulation of protein aggregates by transmission electron microscopy (n=4, each), and B) repression of mitochondrial and endoplasmatic reticulum related genes by genome-wide expression profiling. In cultured ventricular myocytes, atorvastatin, but not pravastatin; 1) down-regulated survival pathways via inhibition of ERK1/2T202/Y204, AktSer473 and mTOR signaling (p70 S6 kinaseThy421/Ser4240 and S6 RPSER 235/236), 2) reduced protein expression of caveolin-1, dystrophin, epithermal growth factor receptor and insulin receptor β, 3) decreased RhoA activation, and 4) induced apoptosis.
LDL-C reduction by atorvastatin, but not pravastatin, was associated with a repression of mitochondrial and endoplasmic reticulum related genes, an accumulation of protein aggregates, and swollen mitochondria. This is the first report demonstrating that long-term atorvastatin treatment causes adverse effects on cardiac muscle with preserved cardiac function. Whether these changes predispose atorvastatin treated hearts to contractile dysfunction after hemodynamic stress needs further investigation.