Fenofibrate induces plaque regression in hypercholesterolemic atherosclerotic rabbits: In vivo demonstration by high-resolution MRI

Roberto Corti, Julio Osende, Randolph Hutter, Juan F. Viles-Gonzalez, Urooj Zafar, Carolina Valdivieso, Gabor Mizsei, John T. Fallon, Valentin Fuster, Juan J. Badimon

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Introduction: Fenofibrate has shown to reduce major cardiovascular events and slow angiographic progression of coronary atherosclerosis. The postulated mechanism of action is via the activation of peroxisomal proliferator-activated receptor-α (PPAR-α), a nuclear transcription factor that controls a variety of cellular functions. We investigated the anti-atherogenic effects of fenofibrate on previously established experimental atherosclerotic lesions. Method: Atherosclerotic lesions were induced in the abdominal aorta of New Zealand white (NZW) rabbits (n = 19) by a combination of a double-balloon injury and a 9-month hypercholesterolemic diet. The rabbits were randomized into placebo or fenofibrate group. The corresponding treatments were added to the hypercholesterolemic diet. All rabbits underwent MRI examination at randomization and after 6 months of treatment, and were then sacrificed for histopathology. Results: LDL-cholesterol was similarly elevated at randomization and follow-up, and was not significantly modified by fenofibrate therapy. HDL-cholesterol decreased (-27 ± 10%, p = 0.04) in the placebo and increased (+36.8 ± 2%, p = 0.04) in the fenofibrate group. MRI showed comparable vessel wall area (VWA) at randomization in both groups. At 15 months, a significant increase in VWA was seen in the placebo group (15 ± 4%, p = 0.007), while fenofibrate treatment was associated with a regression (-11 ± 4%, p = 0.041) of previously established lesions. Fenofibrate also decreased macrophage and increased smooth muscle cell/collagen content of atherosclerotic lesions. Conclusion: MRI measurements can, in conjunction with in vitro histological measurements, contribute to the understanding of the actions of pharmacologic agents in experimental models of atherosclerosis. Fenofibrate significantly regresses atherosclerotic lesions and induced changes in plaque composition associated with a more "stable" phenotype (reduced macrophages and increased SMC). These observations support the potential anti-atherogenic effects of PPAR-α agonists.

Original languageEnglish (US)
Pages (from-to)106-113
Number of pages8
JournalAtherosclerosis
Volume190
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Aorta
  • Atherosclerosis
  • Fenofibrate
  • Lipid lowering
  • MRI

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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