Therapeutic potential for recombinant apoA-I Milano in aortic stenosis

Short-term infusion of recombinant apolipoprotein A-I Milano (rApoA-IMilano), a mutant form of ApoA-I, the main apolipoprotein in HDL, rapidly reversed aortic stenosis in an experimental model. Reduced inflammation and calcification appeared to mediate these beneficial effects. The study was reviewed by HDL Forum Editor Professor Kerry-Anne Rye, Heart Research Institute, Sydney Australia.

 Speidl WS, Cimmino G, Ibanez B et al. Recombinant apolipoprotein A-I Milano rapidly reverses aortic stenosis and decreases leaflet inflammation in an experimental rabbit model. European Heart J 2010. Published on-line March 19, 2010.

 Aortic stenosis (AS) confers substantial morbidity and mortality, especially in the elderly population. However, surgical intervention is often contraindicated in this group.1 Therefore, alternative approaches are needed for the management of AS.

Carriers of  ApoA-IMilano have very low plasma levels of HDL cholesterol but paradoxically, no increase in the risk of heart disease. Consequently, reconstituted HDL (rHDL) containing ApoA-I complexed with lipid (to reduce clearance form the circulation) has been investigated as a potential therapeutic agent. Experimental studies showed that rHDL containing ApoA-IMilano reduced pre-existing lipid-rich plaques, and stabilised ‘vulnerable’ plaques, in addition to exhibiting pleiotropic effects, including antinflammatory activity. In small clinical trials, rHDL containing ApoA-IMilano also reduced plaque build-up on arterial walls.2

 In this study, the authors used a hypercholesterolemic rabbit model of AS. Rabbits were fed an atherogenic diet over 9 months, and echocardiography was then used to verify the existence of AS. The rabbits were then randomly allocated to intravenous infusion with rHDL containing ApoA-IMilano phospholipids (2 x ETC-216 75 mg/kg, n=12) or placebo (saline, n=8), given 4 days apart. Echocardiography was repeated 4 days after the second injection.

 Post-mortem examination showed that the group treated with rApoA-IMilano had a significant 32% increase in aortic valve area (p<0.01) whereas there was essentially no change in the placebo group (Table 1).

 On histological examination, the ApoA-IMilano group had less aortic valve leaflet thickening (0.20 ± 0.07 mm vs. 0.29 ± 0.05 mm, p<0.01) and reduced inflammation compared with the placebo group. Aortic valve calcification was evident in only 25% (3 of 12) rabbits in the ApoA-IMilano group versus 88% (7 of 8) rabbits in the placebo group).

 To evaluate the potential mechanisms underlying these effects, the authors cultured porcine aortic valve myofibroblasts with oxidized low-density lipoproteins. This produced an increase in expression of monocyte chemoattractant protein-1, nuclear factor-kB, and alkaline phosphatase. However, previous exposure to rApoA-IMilano  inhibited these effects, and also significantly reduced intracellular cholesterol content.

 The authors concluded that the beneficial effect of ApoA-IMilano in reversing AS in this experimental model appears to be mediated by enhanced cholesterol removal and reduced inflammation and calcification. Although acknowledging the limitations of extrapolating data from an animal model to the clinical setting, the authors concluded that HDL/ApoA-I-based interventions have potential benefits for the management of fibrocalcific aortic valve disease. Their findings are especially relevant given the increasing prevalence of this condition in an aging population.

References

1. Iung B, Cachier A, Baron G et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714-20.

2. Calabresi L, Sirtori CR, Paoletti R, Franceschini G. Recombinant apolipoprotein A‑IMilano for the treatment of cardiovascular diseases. Curr Athero Rep 2006;8: 163-7.


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