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Can Statins Alter Coronary Plaque Composition Assessed by Radiofrequency Backscatter Intravascular Ultrasound?^_*

Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia

Key Words: atherosclerosis • imaging • lipids • lipoprotein • plaque

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce serum low-density lipoprotein (LDL) and major adverse cardiac events (MACE) by 30% to 50% (3,4). Although the mechanisms by which statins confer this benefit have not been fully elucidated, regression and/or halting progression of coronary plaque volume, stabilization of vulnerable plaques, as well as pleiotropic effects such as reduction in systemic inflammation and oxidative stress, and improvement of endothelial function are presumed to play important roles.

A number of imaging modalities, including computerized tomography (5), angiography (6), and intravascular ultrasound (IVUS) have been deployed to evaluate the effects of therapies on coronary atherosclerosis. With its high spatial resolution (100 to 120 µm) and ability to image vessel wall, IVUS has emerged as the gold standard for quantitative assessment of coronary atherosclerosis. Several prospective studies have shown a correlation between the degree of LDL lowering by statins and their effects on reducing progression and/or inducing plaque regression (7–10). However, there is discrepancy between the large reduction in MACE with statins and their modest, if any, effect on plaque regression.

Therefore it seems logical to assume that statins must have a significant impact in stabilizing plaque by altering its composition. With grayscale IVUS to assess plaque composition, Schartl et al. (7) found that patients receiving atorvastatin had significantly greater increase in hyperechoic (assumed fibrous) plaque compared with patients receiving usual care. A study using optical coherence tomography demonstrated that 9 months of statin therapy in patients with ACS results in greater increases in plaque fibrous cap thickness of nonculprit lesions compared with placebo (11). Angioscopy has also demonstrated a significant decrease in yellow lipid plaque in patients treated with atorvastatin.

Recently, spectral analysis of radiofrequency backscatter IVUS has been developed in an attempt to derive more information on plaque composition compared with grayscale IVUS. Both major IVUS companies have developed software to provide information on plaque characterization: virtual histology (VH) IVUS by Volcano Corporation (Rancho Cordova, California), and IVUS integrated backscatter (IB) by Boston Scientific (Natick, Massachusetts). The VH-IVUS has been compared with ex vivo human coronary histology (12), directional coronary atherectomy specimens (13), and carotid end-atherectomy specimens (14), with predictive accuracies of 88% to 93% for detecting necrotic core, fibro-fatty, fibrous, and calcified plaques. One previously published study using IVUS-IB demonstrated a significant reduction in percent lipid plaque volume over 6 months in patients treated with Atorvastatin or Pravastatin (15).

In this issue of JACC: Cardiovascular Interventions, 2 papers evaluate the effect of statins on VH-IVUS plaque composition. The first study by Nasu et al. (16) was a nonrandomized, open-labeled study evaluating the effects of 12 months of fluvastatin therapy (60 mg/day) on VH-IVUS plaque composition of nonculprit lesions. Forty patients with serum cholesterol >220 mg/dl or LDL >140 mg/dl were treated with fluvastatin, and the remaining 40 patients were treated with placebo. Mean cholesterol and high-sensitivity C-reactive protein (hs-CRP) levels were significantly reduced in the fluvastatin group. The authors found 8% regression in plaque plus media volume in the fluvastatin group and a 2.5% progression of plaque plus media volume in the placebo group. Analysis of VH-IVUS data in the fluvastatin group revealed a significant 59% relative reduction in plaque fibro-fatty volume and significant 11% increase in plaque fibrous tissue volume, with no significant change in necrotic core volume or calcium volume. Interestingly, the change in fibro-fatty plaque volume correlated significantly with change in LDL cholesterol level (r = 0.70, p < 0.0001) and with change in hs-CRP (r = 0.36, p < 0.01).

The second study by Hong et al. (17) was a randomized study comparing the effects of 12 months of simvastatin (20 mg/day, n = 50) with rosuvastatin (10 mg/day, n = 50) on VH-IVUS plaque composition of mild nonculprit lesions in patients with stable angina or ACS. At 12 months, the authors found significantly lower cholesterol and LDL levels in patients with rosuvastatin compared with simvastatin; however, there were no significant differences in plaque volume or plaque composition between the groups at 12 months. When baseline and follow-up data were compared among all 100 study patients, there was a significant 3% reduction in plaque plus media volume with statin therapy over 12 months, significant 16% reduction in plaque necrotic core volume, and significant 28% increase in plaque fibro-fatty volume, with no significant change in plaque fibrous or calcium content.

With regard to the effect of the statins on grayscale IVUS plaque volumes, both studies report significant regression of mean plaque volume: 8% with fluvastatin 60 mg/day, 3.9% with rosuvastatin 10 mg/day, and 2% with simvastatin 20 mg/day. These levels of plaque regression seem to be in keeping with the existing grayscale IVUS published data. For comparison with the current papers, one can compare the secondary or co-primary end points of change in atheroma volume in the 10-mm segment with greatest disease severity from REVERSAL (Reversal of Atherosclerosis With Aggressive Lipid Lowering) and ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) trials, respectively (8,9). If one uses this IVUS end point, Nissen et al. (8,9) demonstrated 2.3% mean plaque regression with pravastatin 40 mg/day, 5.9% mean plaque regression with atorvastatin 80 mg/day, and 8.5% mean plaque regression with rosuvastatin 40 mg/day.

The striking differences between the 2 articles are in the effects of statins on VH-IVUS defined plaque composition. Nasu et al. (16) demonstrated a dramatic 59% relative reduction in plaque fibro-fatty volume, a significant 11% relative increase in plaque fibrous tissue volume, and no significant change in plaque necrotic core or calcium content, whereas Hong et al. (17) found a significant 13% relative reduction in plaque necrotic core volume and a significant 27% relative increase in plaque fibro-fatty content and no significant change in plaque fibrous content. So, do statins reduce plaque necrotic core or fibro-fatty content as defined by VH-IVUS? Do they increase fibro-fatty content or fibrous content as defined by VH-IVUS?

At first glance these studies seem at odds with each other. However, there could be several explanations for these apparent discrepancies. First, these investigators studied vastly different patient populations. The study by Hong et al. (17) included a large proportion of patients with ACS (42%), whereas the Nasu et al. (16) study excluded such patients. Secondly, the baseline VH-IVUS plaque compositions of the 2 populations were starkly different. The Hong et al. (17) population at baseline had 29% plaque necrotic core and only 8.5% fibro-fatty content, whereas the study by Nasu et al. had the reverse composition, with only 8.3% necrotic core and 24.5% fibro-fatty content. The reason the Hong et al. (17) study has significantly greater necrotic core is likely because they had a large portion of ACS patients and they restricted their analysis to the 10-mm segment of most severe disease. One is much more likely to get a significant change in an end point when starting out with more of that variable.

Beyond this statistical effect, is it possible that statins have differing effects on patients with stable atherosclerotic plaque than patients with ACS who have large pools of necrotic lipid cores in their plaques? One can speculate that, in the stable plaques, statins seem to replace plaque fibro-fatty content with fibrous tissue to a degree that closely correlates with both LDL- and hs-CRP–lowering, and in ACS patients with higher necrotic core content, statins might convert the necrotic lipid core to more stable fibro-fatty content. Clearly, these findings and speculations are hypothesis-generating and would need to be confirmed in larger randomized studies.

Another important difference between the 2 studies relates to the relative effectiveness and/or pleiotropic effects of different statins. Patients in the Nasu et al. (16) study had higher LDL levels at the start and end of the study (145 mg/dl and 98 mg/dl, respectively) compared with the Hong et al. (17) population (LDL levels 118 mg/dl at start, and 70 mg/dl at study end). It is possible that fluvastatin versus simvastatin versus rosuvastatin at the doses used might have differing effects on plaque composition. Furthermore, other risk factors and therapies that might affect plaque composition were either not similar between the studies or not described. For instance, how aggressively were diabetes, hypertension, and smoking treated in each study? What percent of diabetic patients in either study were treated with Pioglitazone, a drug that has been reported to affect plaque necrotic core progression (18)? More patients in the Nasu et al. (16) study received drugs such as angiotensin-converting enzyme inhibitors (40% vs. 26%) and angiotensinogen II receptor blockers (40% vs. 21%), which might also have significant independent effects on plaque progression and composition. Thus, comparing changes in plaque composition across different patient populations and studies can be misleading.

An additional explanation for the different results in these studies could be the variability in VH-IVUS measurements. Although the Nasu et al. (16) paper describes simple grayscale IVUS intraobserver variability data, neither article reported on their intraobserver and interobserver variability of individual VH-IVUS components, which could be substantial (19). In addition, the motorized pullback devices have variable pullback length reproducibility that might affect plaque volume measurement (20).

Despite some limitations, the studies by Nasu et al. (16) and Hong et al. (17) provide novel insights into the differential effects of statins on plaque composition in various atherosclerotic phenotypes. They have added to the limited existing published data of the effects of anti-atherosclerotic therapies on spectral analysis of radiofrequency backscatter IVUS for in vivo plaque characterization (Table 1) and complement gray scale IVUS, optical coherence tomography, and angioscopy data (7,11,15,18, 21–23). Further investigation of the effects of statins on plaque composition will be performed in studies such as SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin Versus AtorvastatiN), a multicenter study evaluating the impact of 40-mg rosuvastatin and 80-mg atorvastatin on the progression of atherosclerosis in approximately 1,300 patients.

	Footnotes

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

^_* Reprint requests and correspondence: Dr. Habib Samady, Associate Professor of Medicine, Emory University School of Medicine, Suite F606, 1365 Clifton Road, Atlanta, Georgia 30322 (Email: hsamady{at}emory.edu).

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