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EDITORIAL COMMENT

ApoA-I_Milano/Phospholipid Complex

Clinical Implications of Dose-Response Studies in Rabbit Atherosclerosis With Intravascular Ultrasound and Magnetic Resonance Imaging^_*

Department of Medicine, Cardiology Division, University of Washington, School of Medicine, Seattle, Washington.

^_* Reprint requests and correspondence: Dr. Xue-Qiao Zhao, University of Washington, 1914 North 34th Street, Suite 204, Seattle, Washington 98103. (Email: xueqiao{at}u.washington.edu).

This dose-finding study demonstrated significant plaque regression, about 6%, in ETC-216–treated rabbits compared with placebo with each technique. The minimally effective dose was 40 mg/kg. The rapid-onset effective dose was 150 mg/kg. Five infusions seemed to be necessary. The authors of this study partially confirmed previous ETC-216–induced plaque regression (3,4). However, they did not use MRI’s tissue-composition capabilities (5,6) to document the mechanism of shrinkage.

A similar report by Ibanez et al. (7) asks whether ETC-216 infusions acutely change plaque size, cell morphology, or expression of genes and proteins, potentially contributing to plaque vulnerability. In a similar aortic injury model of advanced atherosclerosis, rabbits were randomized to 2 infusions, separated by 4 days, of 75 mg/kg ETC-216 or placebo. Aortic plaques (celiac to iliac level) were imaged with MRI before and after the infusions, and their area was measured with the use of semiautomated visual border-definition. Aortic cellular composition and gene expression markers were subsequently assessed histologically. Relative to placebo, which had no effect, ETC-216 infusions reduced mean plaque area by 5% from pre-treatment (p = 0.003). This effect compares to a previously reported 12% (p < 0.05) and 22% (p < 0.01) plaque area reduction in this model after 6 months treatment with simvastatin ± a peroxisomal proliferator-activated receptor-gamma agent (8), and to 4% coronary plaque reduction in patients (9). Macrophage density and gene and protein expression of tissue factor, monocyte chemoattractant protein–1, cyclooxygenase-2, and gelatinase, all putative markers of plaque vulnerability, were measurably reduced.

These 2 studies found consistent and significant plaque regression, approximately 6%, in ETC-216–treated animals, compared with placebo. The plaque regression was assessed by 2 different and reliable imaging modalities (intravascular ultrasound and MRI) in both carotids and aortas. Favorable changes in plaque area and in markers of vulnerability were observed after only 2 administrations of ETC-216. These results support the idea that these infusions are rapidly effective in modestly reducing atherosclerosis burden.

A crucial question is whether the 6% plaque regression found in these 2 studies is biologically or clinically meaningful. Experimental atherosclerosis in rabbits differs markedly from human plaques. The rabbits’ atherosclerosis, induced over several months, comprises nearly 90% cholesterol-enriched foam cells (2) that are more easily lipid-depleted (10). However, removable plaque components (lipid) represent only 13% to 16% of the average human plaque (11). Thus, human plaque volume is probably less responsive to ETC-216, to be considered in planning future human studies.

If this amount of plaque shrinkage is due to reductions in plaque core lipid, foam cell density, and inflammatory activities, this should benefit clinical outcomes, because 60% to 90% of unstable clinical episodes are due to disruption and thrombosis of lipid-rich plaques, which represent approximately 15% of human coronary lesions (>50% lipid by volume) (12,13). Long-term intensive lipid therapy is associated with markedly, and selectively, reduced plaque lipid content assessed by MRI (14). These patients also have significantly reduced cardiovascular death and myocardial infarction frequency compared with those given usual care (15). Other lipid therapy trials that use quantitative arteriography (16–18) have demonstrated that coronary disease regression is correlated with a reduction in low-density lipoprotein cholesterol, an increase in high-density lipoprotein (HDL) cholesterol, and with a reduction in coronary events. If the authors of these 2 studies (1,7) had used MRI’s capability to resolve tissue composition, they might have confirmed that the 6% regression was entirely due to plaque lipid depletion.

Another critical question is whether partially delipidated homologous or even autologous apolipoprotein (apo) A-I or a synthetic nascent HDL particle (2 apoA-I molecules bound by phospholipids) or oral apoA-I-mimetic peptides (19) would work as well as the ETC-216 particle for depletion of plaque lipid or inhibition of inflammation (20) or of endothelial cell adhesion molecules (21). However, the unique molecular structure of apoA-I_Milano (22) may convey unique properties. Despite very low HDL cholesterol levels, apoA-I_Milano carriers do not display features of impaired vascular function, such as elevated levels of soluble cell adhesion molecules, increased tumor necrosis factor-, or reduced endothelial nitric oxide synthase expression (23), and they do not demonstrate the anticipated cardiovascular complications (24).

Finally, because of cost, inconvenience, and possible antigenic effects, it is highly unlikely that chronic apoAI/phospholipid infusions would substitute for lipid drug therapy as a chronic prevention strategy. If, however, the immediate clinical benefits of acute apoAI infusions are established in phase-3 trials, with a defined agent, dose, and dosing sequence, then such infusions would most likely be used in the early aftermath of an acute coronary syndrome (ACS). During the first 6 to 8 months after ACS, the coronary event rate is at least twice as great as that in the subsequent chronic follow-up period (25,26). If apoAI infusions are found to deplete plaque lipid and to stabilize vulnerable plaque more rapidly and effectively than the current standard post-ACS therapy, then this approach, as an adjunctive to pharmacologic lipid-altering therapy, may have merit. On the basis of these 2 reports (1,7), the likely regimen will be the human equivalent of the 40- to 75-mg/kg rabbit dose, administered 4 to 5 times at plasma half-life intervals. Methods for more selective delivery may be developed. Much work remains.

	Footnotes

 
Supported in part by NIH Grants R01 HL063895 and R01 HL088214.

^_* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

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