The effects of 3-month atorvastatin therapy on arterial inflammation, calcification, abdominal adipose tissue and circulating biomarkers

  • Yen-Wen Wu
  • Hsian-Li Kao
  • Chi-Lun Huang
  • Ming-Fong Chen
  • Lian-Yu Lin
  • Yi-Chih Wang
  • Yen-Hung Lin
  • Hung-Ju Lin
  • Kai-Yuan Tzen
  • Ruoh-Fang Yen
  • Yu-Chiao Chi
  • Por-Jau Huang
  • Wei-Shiung Yang
Original Article



18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT has the potential to track vascular inflammation and monitor therapeutic response. The purpose of this study was to determine the association between arterial inflammation, calcification and serological biomarkers in subjects with atherosclerosis, and to assess their therapeutic response to 12-week atorvastatin treatment.


Forty-three statin-naïve subjects with atherosclerosis received atorvastatin (40 mg/day) for 12 weeks and underwent 18F-FDG PET/CT, coronary calcification and abdominal adipose tissue volume measurements. A panel of serological biomarkers was analysed. Arterial inflammation was measured at seven arterial segments and normalized to venous FDG activity to produce target to background ratios (TBR). Thirty-four subjects without cardiovascular disease who repeated PET 1–4 years apart for routine health check-ups were retrospectively evaluated for comparison.


The baseline mean TBR values in atherosclerotic patients were positively correlated with age (R = 0.36), body mass index (R = 0.54), abdominal visceral adipose tissue volume (R = 0.65), coronary calcification score (R = 0.40), levels of low-density lipoprotein cholesterol (R = 0.54), matrix metalloproteinase (MMP)-9 (R = 0.46) and fatty acid binding protein 4 (FABP4) (R = 0.67, all p < 0.05). The TBR as well as high-sensitivity C-reactive protein (hsCRP), E-selectin, MMP-9, monocyte chemotactic protein 1, FABP4 and follistatin values were reduced significantly after the 12-week atorvastatin treatment. The TBR reduction marginally correlated with changes in MMP-9 levels (R = 0.56, p = 0.05). The control group, whose median age was younger, by comparison had lower hsCRP and arterial TBR than the subjects with atherosclerosis (all p < 0.05), and moreover had a slight but insignificant increase in mean TBR at their 2.5±0.8 year follow-up.


The medium dose of atorvastatin over a 12-week period resulted in a significant reduction of arterial inflammation as well as various circulating biomarkers.


18F-Fluorodeoxyglucose positron emission tomography Inflammation Calcification Biomarker Statin 



This study was supported in part by grant NSC 96-2321-B-002-029-MY2, NSC 98-2314-B-002-145-MY2 from the National Science Council of Taiwan and Pfizer Limited (Taiwan). The authors acknowledge the assistance provided by the National Taiwan University Hospital, Center for PET and Health Management Center staff.

Conflicts of interest

This study is in part supported by Pfizer Limited (Taiwan).


  1. 1.
    Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R, Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78.PubMedCrossRefGoogle Scholar
  2. 2.
    Takano M, Mizuno K, Yokoyama S, Seimiya K, Ishibashi F, Okamatsu K, Uemura R. Changes in coronary plaque color and morphology by lipid-lowering therapy with atorvastatin: serial evaluation by coronary angioscopy. J Am Coll Cardiol 2003;42:680–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Okazaki S, Yokoyama T, Miyauchi K, Shimada K, Kurata T, Sato H, Daida H. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation 2004;110:1061–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Lombardo A, Biasucci LM, Lanza GA, Coli S, Silvestri P, Cianflone D, et al. Inflammation as a possible link between coronary and carotid plaque instability. Circulation 2004;109:3158–63.PubMedCrossRefGoogle Scholar
  5. 5.
    Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, Yates D, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 2006;48:1818–24.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen W, Bural GG, Torigian DA, Rader DJ, Alavi A. Emerging role of FDG-PET/CT in assessing atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging 2009;36:144–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Saam T, Rominger A, Wolpers S, Nikolaou K, Rist C, Greif M, et al. Association of inflammation of the left anterior descending coronary artery with cardiovascular risk factors, plaque burden and pericardial fat volume: a PET/CT study. Eur J Nucl Med Mol Imaging 2010;37:1203–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Tahara N, Kai H, Yamagishi S, Nakaura H, Ishibashi M, Kaida H, et al. Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. J Am Coll Cardiol 2007;49:1533–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Kim TN, Kim S, Yang SJ, Yoo HJ, Seo JA, Kim SG, et al. Vascular inflammation in patients with impaired glucose tolerance and type 2 diabetes: analysis with 18F-fluorodeoxyglucose positron emission tomography. Circ Cardiovasc Imaging 2010;3:142–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Rudd JH, Myers KS, Bansilal S, Machac J, Woodward M, Fuster V, et al. Relationships among regional arterial inflammation, calcification, risk factors, and biomarkers: a prospective fluorodeoxyglucose positron-emission tomography/computed tomography imaging study. Circ Cardiovasc Imaging 2009;2:107–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Wu YW, Kao HL, Chen MF, Lee BC, Tseng WY, Jeng JS, et al. Characterization of plaques using 18F-FDG PET/CT in patients with carotid atherosclerosis and correlation with matrix metalloproteinase-1. J Nucl Med 2007;48:227–33.PubMedGoogle Scholar
  12. 12.
    Yoo HJ, Kim SE, Park MS, Choi HY, Yang SJ, Seo JA, et al. Serum adipocyte fatty acid-binding protein is associated independently with vascular inflammation: analysis with 18F-fluorodeoxyglucose positron emission tomography. J Clin Endocrinol Metab 2011;96:E488–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Choi HY, Kim S, Yang SJ, Yoo HJ, Seo JA, Kim SG, et al. Association of adiponectin, resistin, and vascular inflammation: analysis with 18F-fluorodeoxyglucose positron emission tomography. Arterioscler Thromb Vasc Biol 2011;31:944–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Yoo HJ, Kim S, Park MS, Yang SJ, Kim TN, Seo JA, et al. Vascular inflammation stratified by C-reactive protein and low-density lipoprotein cholesterol levels: analysis with 18F-FDG PET. J Nucl Med 2011;52:10–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Paulmier B, Duet M, Khayat R, Pierquet-Ghazzar N, Laissy JP, Maunoury C, et al. Arterial wall uptake of fluorodeoxyglucose on PET imaging in stable cancer disease patients indicates higher risk for cardiovascular events. J Nucl Cardiol 2008;15:209–17.PubMedCrossRefGoogle Scholar
  16. 16.
    Rominger A, Saam T, Wolpers S, Cyran CC, Schmidt M, Foerster S, et al. 18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease. J Nucl Med 2009;50:1611–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Grandpierre S, Desandes E, Menerous B, Djaballah W, Mandry D, Netter F, Wahl D, et al. Arterial foci of F-18 fluorodeoxyglucose are associated with an enhanced risk of subsequent ischemic stroke in cancer patients: a case-control pilot study. Clin Nucl Med 2011;36:85–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Rudd JH, Myers KS, Bansilal S, Machac J, Rafique A, Farkouh M, et al. (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials. J Am Coll Cardiol 2007;50:892–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Ogawa M, Magata Y, Kato T, Hatano K, Ishino S, Mukai T, et al. Application of 18F-FDG PET for monitoring the therapeutic effect of antiinflammatory drugs on stabilization of vulnerable atherosclerotic plaques. J Nucl Med 2006;47:1845–50.PubMedGoogle Scholar
  20. 20.
    Zhao Y, Kuge Y, Zhao S, Strauss HW, Blankenberg FG, Tamaki N. Prolonged high-fat feeding enhances aortic 18F-FDG and 99mTc-annexin A5 uptake in apolipoprotein E-deficient and wild-type C57BL/6J mice. J Nucl Med 2008;49:1707–14.PubMedCrossRefGoogle Scholar
  21. 21.
    Worthley SG, Zhang ZY, Machac J, Helft G, Tang C, Liew GY, et al. In vivo non-invasive serial monitoring of FDG-PET progression and regression in a rabbit model of atherosclerosis. Int J Cardiovasc Imaging 2009;25:251–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Tahara N, Kai H, Ishibashi M, Nakaura H, Kaida H, Baba K, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006;48:1825–31.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee SJ, On YK, Lee EJ, Choi JY, Kim BT, Lee KH. Reversal of vascular 18F-FDG uptake with plasma high-density lipoprotein elevation by atherogenic risk reduction. J Nucl Med 2008;49:1277–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336–45.PubMedCrossRefGoogle Scholar
  25. 25.
    Hoffmann U, Siebert U, Bull-Stewart A, Achenbach S, Ferencik M, Moselewski F, et al. Evidence of lower variability of coronary artery calcium mineral mass measurement by multi-detector computed tomography in a community-based cohort: consequences for progression studies. Eur J Radiol 2006;57:396–402.PubMedCrossRefGoogle Scholar
  26. 26.
    Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007;116:39–48.PubMedCrossRefGoogle Scholar
  27. 27.
    Pou KM, Massaro JM, Hoffmann U, Vasan RS, Maurovich-Horvat P, Larson MG, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation 2007;116:1234–41.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, O’Donnell CJ, Fox CS. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation 2008;117:605–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Detrano RC, Wong ND, Doherty TM, Shavelle RM, Tang W, Ginzton LE, et al. Coronary calcium does not accurate predict near-term future coronary events in high-risk adults. Circulation 1999;99:2633–8.PubMedGoogle Scholar
  31. 31.
    Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009;373:1175–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Sluijter JP, Pulskens WP, Schoneveld AH, Velema E, Strijder CF, Moll F, et al. Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms. Stroke 2006;37:235–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Græbe M, Pedersen SF, Borgwardt L, Højgaard L, Sillesen H, Kjær A. Molecular pathology in vulnerable carotid plaques: correlation with [18]-fluorodeoxyglucose positron emission tomography (FDG-PET). Eur J Vasc Endovasc Surg 2009;37:714–21.PubMedCrossRefGoogle Scholar
  34. 34.
    Kajimoto K, Miyauchi K, Kasai T, Shimada K, Kojima Y, Shimada A, et al. Short-term 20-mg atorvastatin therapy reduces key inflammatory factors including c-Jun N-terminal kinase and dendritic cells and matrix metalloproteinase expression in human abdominal aortic aneurysmal wall. Atherosclerosis 2009;206:505–11.PubMedCrossRefGoogle Scholar
  35. 35.
    Massaro M, Zampolli A, Scoditti E, Carluccio MA, Storelli C, Distante A, De Caterina R. Statins inhibit cyclooxygenase-2 and matrix metalloproteinase-9 in human endothelial cells: anti-angiogenic actions possibly contributing to plaque stability. Cardiovasc Res 2010;86:311–20.PubMedCrossRefGoogle Scholar
  36. 36.
    Llaverias G, Noé V, Peñuelas S, Vázquez-Carrera M, Sánchez RM, Laguna JC, et al. Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages. Biochem Biophys Res Commun 2004;318:265–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Krysiak R, Labuzek K, Okopień B. Effect of atorvastatin and fenofibric acid on adipokine release from visceral and subcutaneous adipose tissue of patients with mixed dyslipidemia and normolipidemic subjects. Pharmacol Rep 2009;61:1134–45.PubMedGoogle Scholar
  38. 38.
    Peeters W, de Kleijn DP, Vink A, van de Weg S, Schoneveld AH, Sze SK, et al. Adipocyte fatty acid binding protein in atherosclerotic plaques is associated with local vulnerability and is predictive for the occurrence of adverse cardiovascular events. Eur Heart J 2011;32:1758–68.PubMedCrossRefGoogle Scholar
  39. 39.
    Eijken M, Swagemakers S, Koedam M, Steenbergen C, Derkx P, Uitterlinden AG, et al. The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J 2007;21:2949–60.PubMedCrossRefGoogle Scholar
  40. 40.
    Widera C, Horn-Wichmann R, Kempf T, Bethmann K, Fiedler B, Sharma S, et al. Circulating concentrations of follistatin-like 1 in healthy individuals and patients with acute coronary syndrome as assessed by an immunoluminometric sandwich assay. Clin Chem 2009;55:1794–800.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Yen-Wen Wu
    • 1
    • 2
  • Hsian-Li Kao
    • 1
  • Chi-Lun Huang
    • 3
  • Ming-Fong Chen
    • 1
  • Lian-Yu Lin
    • 1
  • Yi-Chih Wang
    • 1
  • Yen-Hung Lin
    • 1
  • Hung-Ju Lin
    • 1
  • Kai-Yuan Tzen
    • 2
  • Ruoh-Fang Yen
    • 2
  • Yu-Chiao Chi
    • 4
  • Por-Jau Huang
    • 1
  • Wei-Shiung Yang
    • 1
    • 4
  1. 1.Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
  2. 2.Department of Nuclear MedicineNational Taiwan University HospitalTaipeiTaiwan
  3. 3.Department of Internal MedicineTao-Yuan General HospitalTao-YuanTaiwan
  4. 4.Graduate Institute of Clinical Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan

Personalised recommendations