Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model

Walter S. Speidl, Giovanni Cimmino, Borja Ibanez, Sammy Elmariah, Randolph Hutter, Mario J. Garcia, Valentin Fuster, Martin E. Goldman, Juan J. Badimon

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Aims Aortic stenosis (AS) is associated with significant morbidity and mortality. Recombinant apolipoprotein A-I Milano (rApoA-IM) induces atherosclerotic plaque regression. The Aims of this study were to determine the effects of rApoA-IM on experimental aortic valve degeneration and its mechanisms of action. Methods and results New Zealand White rabbits (n = 20) were fed an atherogenic diet for 9 months and then randomized to either placebo or rApoA-IM. Echocardiography was used to assess the effect of the treatments on AS. Porcine aortic valve myofibroblasts (PAVMF) treated with oxidized low-density lipoprotein served to define the effects of rApoA-IM on the expression of monocyte chemoattractant protein-1 (MCP-1), nuclear factor (NF)-B, and alkaline phosphatase (AP). Recombinant apolipoprotein A-I Milano increased aortic valve area (AVA) by 32 (0.25 ± 0.05 to 0.34 ± 0.07 cm2, P < 0.01); whereas AVA remained unchanged in the placebo group (0.24 ± 0.05 to 0.26 ± 0.04 cm2, P = 0.58). Histopathological examination of aortic valves in the rApoA-IM animals showed significantly less leaflet thickening, inflammation, and calcification vs. the placebo group. In vitro, rApoA-IM significantly inhibited MCP-1, AP, and NF-B and decreased intracellular cholesterol content in PAVMF. Conclusion Recombinant apolipoprotein A-I Milano treatment reverses AS in this experimental rabbit model. The beneficial effects seem to be mediated by enhanced cholesterol removal and by reduced inflammation and calcification.

Original languageEnglish (US)
Pages (from-to)2049-2057
Number of pages9
JournalEuropean heart journal
Volume31
Issue number16
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

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Keywords

  • Aortic valve stenosis
  • Apolipoprotein A-I Milano
  • Calcification
  • Inflammation
  • Myofibroblast

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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