The PPARα activator fenofibrate fails to alter myocardial metabolism in healthy individuals despite marked peripheral effects

Objectives Peroxisome proliferator-activated receptor-α (PPARα) regulates the expression of fatty acid oxidation genes in both the liver and the heart. Though rodent studies suggest that PPARα activation with fenofibrate modulates both cardiac and hepatic metabolism, in large animal models fenofibrate does not alter myocardial metabolism in spite of marked systemic metabolic effects. Whether fenofibrate alters myocardial metabolism in humans is unclear.

Methods We studied 18 younger and 17 older, healthy volunteers (ages 21-35 & 60-75y, respectively). Myocardial oxygen consumption (MVO₂) as well as fatty acid utilization (MFAU) and oxidation (MFAO) were quantified by positron emission tomography at baseline and after 7 and 30 days of fenofibrate (145 mg daily). Cardiac work was measured by echocardiography,and efficiency was calculated as work/MVO₂.

Results Fenofibrate improved the lipid profile in all groups but failed to alter plasma substrates, insulin or myocardial fatty acid metabolism (TABLE). MVO₂ was higher in older individuals at baseline and increased further after 30 days fenofibrate therapy (P < 0.01). Nevertheless, no change in efficiency was detected.

Conclusions Despite the systemic effects of fenofibrate in both younger and older individuals, treatment with this PPARα activator does not alter myocardial metabolism or efficiency. These data are consistent with large animal studies suggesting that cardiovascular benefits of PPARα agonists are mediated by peripheral (hepatic) effects and may have important implications for the proposed use of these agents in reducing myocardial ischemia/reperfusion injury.

Research Support NIH K23 HL077179 (PFS) & R01 AG15466 (RJG)