Coronary Plaque Morphology and the Anti-Inflammatory Impact of Atorvastatin: A Multicenter 18F-Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Study

Parmanand Singh, Hamed Emami, Sharath Subramanian, Pal Maurovich-Horvat, Gergana Marincheva-Savcheva, Hector M Medina, Amr Abdelbaky, Achilles Alon, Sudha S Shankar, James H F Rudd, Zahi A Fayad, Udo Hoffmann, Ahmed Tawakol, Parmanand Singh, Hamed Emami, Sharath Subramanian, Pal Maurovich-Horvat, Gergana Marincheva-Savcheva, Hector M Medina, Amr Abdelbaky, Achilles Alon, Sudha S Shankar, James H F Rudd, Zahi A Fayad, Udo Hoffmann, Ahmed Tawakol

Abstract

Background: Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM.

Methods and results: In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (18F-fluorodeoxyglucose uptake, expressed as target-to-background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean±SEM: 1.95±0.43 versus 1.67±0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline Δtarget-to-background ratio [95% confidence interval]: -0.18 [-0.35 to -0.004] versus 0.09 [-0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose (β=-0.27; P=0.038).

Conclusions: In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703261.

Keywords: atherosclerosis; carotid artery; coronary artery disease; inflammation; positron emission tomography.

© 2016 The Authors.

Figures

Figure 1.
Figure 1.
Study flow. Out of 163 subjects who were initially screened, 83 subjects underwent baseline 18F-flurodeoxyglucose positron emission tomographic (FDG-PET)/computed tomographic (CT) scan followed by statin treatment with atorvastatin. Follow-up FDG-PET scan was performed after 12-wk statin therapy. Seventy-one subjects completed the study, and 68 had evaluable PET/CT images. Thereafter, an independent reader analyzed 55 evaluable coronary and carotid computed tomographic angiography (CTA) images while blinded to PET data.
Figure 2.
Figure 2.
Association between high-risk plaque morphology and 18F-flurodeoxyglucose (FDG) uptake in left main coronary artery (LMCA). LMCA inflammation (target-to-background ratio [TBR]) in the index vessel was significantly higher in subjects with high-risk morphology (HRM) than those without HRM (partially calcified plaque/noncalcified plaque [NCP/PCP]) in the underlying coronary segment as detected by coronary computed tomographic angiography. Error bars represent SEM.
Figure 3.
Figure 3.
Focal 18F-flurodeoxyglucose (FDG) uptake in patients with high-risk plaque morphology in the left main coronary artery (LMCA). Fused positron emission tomographic (PET)/computed tomographic (CT) image showing intense and focal FDG uptake in the LMCA, in orthogonal images (A and B), corresponding maximum intensity projection–reconstructed computed tomography angiographic (CTA) image of LMCA with noncalcified plaque (arrow; C), and axial CTA showing a cross-sectional view (D) of an additional plaque in the right coronary artery manifesting positive remodeling and low attenuation (arrow) in the same subject.
Figure 4.
Figure 4.
Statin therapy results in a greater reduction of 18F-flurodeoxyglucose (FDG) uptake in left main coronary artery (LMCA) with high-risk morphology (HRM). Changes in LMCA target-to-background ratio after 12-wk statin therapy were more pronounced in arteries with HRM in coronary computed tomographic angiography. Error bars represent SEM. NCP indicates noncalcified plaque; and PCP, partially calcified plaque.
Figure 5.
Figure 5.
Extracoronary arterial 18F-flurodeoxyglucose (FDG) uptake parallels left main coronary artery (LMCA) FDG uptake. Index vessel FDG uptake (target-to-background ratio [TBR]) at baseline (A) and changes during the 12-wk treatment period (B) significantly correlated with baseline LMCA TBR and changes in LMCA TBR, respectively.
Figure 6.
Figure 6.
Extracoronary arterial inflammation associates with coronary structural features. The positron emission tomography (PET)/computed tomography (CT)–derived inflammatory signal in the ascending aorta (target-to-background ratio [TBR]) was associated with presence of high-risk coronary plaque features by computed tomography angiographic (CTA) such that subjects with higher aortic TBR (≥median) had increased frequency of high-risk plaque features (positive remodeling or low-attenuation plaque without dense calcification) in the entire coronary tree (43.5% vs 13%; P=0.02).

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