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. 2009 Apr;203(2):387-94.
doi: 10.1016/j.atherosclerosis.2008.07.032. Epub 2008 Aug 5.

Attenuation of inflammation and expansive remodeling by Valsartan alone or in combination with Simvastatin in high-risk coronary atherosclerotic plaques

Yiannis S Chatzizisis  1 , Michael Jonas, Roy Beigel, Ahmet U Coskun, Aaron B Baker, Benjamin V Stone, Charles Maynard, Ross G Gerrity, William Daley, Elazer R Edelman, Charles L Feldman, Peter H Stone
Affiliations

Attenuation of inflammation and expansive remodeling by Valsartan alone or in combination with Simvastatin in high-risk coronary atherosclerotic plaques

Yiannis S Chatzizisis et al. Atherosclerosis. 2009 Apr.

Abstract

Aims: We investigated the role of Valsartan (V) alone or in combination with Simvastatin (S) on coronary atherosclerosis and vascular remodeling, and tested the hypothesis that V or V/S attenuate the pro-inflammatory effect of low endothelial shear stress (ESS).

Methods: Twenty-four diabetic, hyperlipidemic swine were allocated into Early (n=12) and Late (n=12) groups. In each group animals were treated with Placebo (n=4), V (n=4) and V/S (n=4) and followed for 8 weeks in the Early group and 30 weeks in the Late group. Blood pressure, serum cholesterol and glucose were similar across the treatment subgroups. ESS was calculated in plaque-free subsegments of interest (n=109) in the Late group at week 23. Coronary arteries of this group were harvested at week 30, and the subsegments of interest were identified, and analyzed histopathologically.

Results: V alone or with S reduced the severity of inflammation in high-risk plaques. Both regimens attenuated the severity of enzymatic degradation of the arterial wall, reducing the severity of expansive remodeling. V alone or with S attenuated the pro-inflammatory effect of low ESS.

Conclusions: V alone or with S exerts a beneficial effect of reducing and stabilizing high-risk plaque characteristics independent of a blood pressure- and lipid-lowering effect.

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Figures

Figure 1
Figure 1
a.Effect of Valsartan and Valsartan/Simvastatin on the progression of atherosclerotic burden in each medication subgroup. Error bars represent the standard error of mean and p values are provided for the statistically significant results only.. b-d. Effect of Valsartan and Valsartan/Simvastatin on the progression of plaque severity in each medication subgroup. Error bars represent the standard error of mean and p values are provided for the statistically significant results only.
Figure 2
Figure 2
Effect of Placebo (P), Valsartan (V) and Valsartan/Simvastatin (V/S) on the histopathologic characteristics of intermediate lesions and fibroatheromas (FAs). Photomicrographs (a-f) of oil red O- and CD45-stained FAs with inflamed thin fibrous cap at the shoulders (black arrowheads; L=lumen, F=fibrous cap, NC=necrotic core, M=media, A=adventitia, C=calcification). V either alone (c, d) or with S (e, f) reduced inflammation at the necrotic core and fibrous cap. Error bars represent the standard error of mean and p values are provided for the statistically significant results only.
Figure 3
Figure 3
a.IEL disintegration in relation to inflammation in each medication subgroup; P=Placebo, V=Valsartan, V / S=Valsartan/Simvastatin. Error bars represent the standard error of mean and p values are provided for the statistically significant results only, b. Frequency distribution of each IEL grade in inadequate remodeling (Inad), compensatory expansive (Comp), and excessive expansive remodeling (Excess).
Figure 4
Figure 4
Effect of Placebo (P), Valsartan (V) and Valsartan/Simvastatin (V/S) on thehistomorphometric (i.e. intima-to-media ratio) and histomorphologic characteristics (i.e. lipids, inflammation, collagen) of inadequate remodeling (Inad), compensatory expansive (Comp), and excessive expansive remodeling (Excess). Error bars represent the standard error of mean and p values are provided for the statistically significant results only.
Figure 5
Figure 5
Effect of Valsartan (V) alone or with Simvastatin (S) in gene expression of extracellular matrix degrading enzymes and their inhibitors in inadequate remodeling (Inad), compensatory expansive (Comp), and excessive expansive remodeling (Excess); P=Placebo. Error bars represent the standard error of mean and p values are provided for the statistically significant results only.
Figure 6
Figure 6
Severity of inflammation in relation to local baseline ESS in each medication subgroup; P=Placebo, V=Valsartan, V / S=Valsartan/Simvastatin. Error bars represent the standard error of mean and p values are provided for the statistically significant results only.
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