University of California, USA
Title: Statin Toxicity: First report of atorvastatin, but not pravastatin, induced ultrastructural and functional changes in cardiac mitochondria
Biography: Alice Zemljic-Harpf
Background: Statins are amongst the most widely prescribed drugs to reduce LDL-cholesterol for the treatment of cardiovascular disease. Approximately one in five people in the United States between the ages of 45 and 75 take a statin. Like all drugs, statins can cause harmful side effects, such as muscle pain/weakness (statin myopathy), fatigue, nerve pain, and cognitive impairment. Because statin-induced myopathy is known to be associated with reduced oxidative phosphorylation in mitochondria of skeletal muscle we hypothesized that similar effects would occur in cardiac muscle.
Methods and Results: When male mice underwent atorvastatin and pravastatin administration per os for up to 7 months, only long-term atorvastatin, but not pravastatin administration induced: 1) elevated serum creatine kinase, 2) swollen, misaligned, size variable, and disconnected cardiac mitochondria, 3) altered ER-structure, 4) repression of mitochondrial and endoplasmatic reticulum related genes, and 5) 21% increased mortality in cardiac-specific vinculin knockout- mice.
Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48hours. Both statins induced ER-stress, but only atorvastatin: 1) inhibited of ERK1/2T202/Y204, AktSer473 and mTOR signaling, 2) reduced protein abundance of caveolin-1, dystrophin, epidermal growth factor receptor and insulin receptor-β, 3) decreased RhoA activation, and 4) induced apoptosis. In cardiomyocyte-equivalent HL-1 cells atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption.
Conclusion and Clinical Implication: Skeletal muscle biopsies from patients with statin myopathy show increased lipid storage and alters mitochondrial structure. We are the first to demonstrate in vivo that long-term atorvastatin administration altered cardiac ultrastructure, a finding with important clinical implications.