Heart and Vessels

, Volume 30, Issue 2, pp 154–161 | Cite as

High HDL cholesterol level after treatment with pitavastatin is an important factor for regression in carotid intima–media thickness

  • Kenji Okumura
  • Hideto Tsukamoto
  • Hideyuki Tsuboi
  • Haruo Hirayama
  • Haruo Kamiya
  • Masato Watarai
  • Ryoji Ishiki
  • Toyoaki Murohara
  • on behalf of the Samurai Study Investigators
Original Article


This study is a prospective multicenter study designed to investigate the effects of lipid-lowering therapy with pitavastatin on atherosclerotic plaque in patients with coronary heart disease, and to determine which factor is more closely associated with plaque regression. Participants (n = 63) were treated with pitavastatin for 12 months, and the carotid intima–media thickness (IMT) was measured by ultrasound before and after treatment. Mean IMT slightly but significantly decreased (from 0.99 ± 0.33 to 0.94 ± 0.28 mm for overall, P = 0.01) regardless of the presence of pretreatment with other statins. There were no significant relations with hs-CRP, malondialdehyde-LDL, LDL cholesterol, and smaller LDL cholesterol levels despite their decrease by pitavastatin. Decreases in mean IMT were observed significantly more frequently in subjects with high on-treatment HDL cholesterol levels than with low HDL cholesterol levels (P = 0.017). The change in mean IMT tended to be inversely correlated with increments in HDL cholesterol and apolipoprotein A-I. The IMT regression was more often observed in the absence of diabetes and metabolic syndrome. In conclusion, we demonstrated that treatment with pitavastatin attenuated atherosclerotic plaque. This effect was associated with the level of HDL cholesterol, and was stronger in the absence of diabetes and metabolic syndrome in our ischemic heart disease patients.


Intima–media thickness Pitavastatin HDL cholesterol Lipoproteins 



We thank all participants of this Secondary SAMURAI Study (Statin therapy against multi-lipoprotein profiling and atherosclerosis) for their co-operation and patience throughout the trial. The Department of Cardiology of the Nagoya University Graduate School of Medicine received an unrestricted research grant support from KOWA Pharmaceutical Co. Ltd. (Tokyo, Japan).


  1. 1.
    Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143CrossRefPubMedGoogle Scholar
  2. 2.
    Bots ML, Mulder PG, Hofman A, van Es GA, Grobbee DE (1994) Reproducibility of carotid vessel wall thickness measurements: the Rotterdam Study. J Clin Epidemiol 47:921–930CrossRefPubMedGoogle Scholar
  3. 3.
    Smilde TJ, Wollersheim H, Van Langen H, Stalenhoef AF (1997) Reproducibility of ultrasonographic measurements of different carotid and femoral artery segments in healthy subjects and in patients with increased intima–media thickness. Clin Sci (Lond) 93:317–324Google Scholar
  4. 4.
    Bernard S, Serusclat A, Targe F, Charriere S, Roth O, Beaune J, Berthezene F, Moulin P (2005) Incremental predictive value of carotid ultrasonography in the assessment of coronary risk in a cohort of asymptomatic type 2 diabetic subjects. Diabetes Care 28:1158–1162CrossRefPubMedGoogle Scholar
  5. 5.
    Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN (2004) Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291:1071–1080CrossRefPubMedGoogle Scholar
  6. 6.
    Nozue T, Yamamoto S, Tohyama S, Fukui K, Umezawa S, Onishi Y, Kunishima T, Sato A, Nozato T, Miyake S, Takeyama Y, Morino Y, Yamauchi T, Muramatsu T, Hirano T, Hibi K, Terashima M, Michishita I (2013) Impacts of age on coronary atherosclerosis and vascular response to statin therapy. Heart Vessels. doi: 10.1007/s00380-013-0387-1
  7. 7.
    Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF (2001) Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357:577–581CrossRefPubMedGoogle Scholar
  8. 8.
    Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM (1988) Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 260:1917–1921CrossRefPubMedGoogle Scholar
  9. 9.
    Koba S, Yokota Y, Hirano T, McNamara JR, Jenner JL, Ordovas JM, Wilson PW, Schaefer EJ (2008) Small LDL-cholesterol is superior to LDL-cholesterol for determining severe coronary atherosclerosis. J Atheroscler Thromb 15:250–260CrossRefPubMedGoogle Scholar
  10. 10.
    Okazaki M, Usui S, Ishigami M, Sakai N, Nakamura T, Matsuzawa Y, Yamashita S (2005) Identification of unique lipoprotein subclasses for visceral obesity by component analysis of cholesterol profile in high-performance liquid chromatography. Arterioscler Thromb Vasc Biol 25:578–584CrossRefPubMedGoogle Scholar
  11. 11.
    Takahashi R, Imamura A, Yoshikane M, Suzuki M, Murakami R, Cheng XW, Numaguchi Y, Ikeda N, Murohara T, Okumura K (2010) Very small low-density lipoprotein cholesterol level is a determinant of arterial stiffness in men with impaired glucose metabolism. J Atheroscler Thromb 17:1282–1289CrossRefPubMedGoogle Scholar
  12. 12.
    Takahashi R, Taguchi N, Suzuki M, Cheng XW, Numaguchi Y, Tsukamoto H, Ikeda N, Murohara T, Okumura K (2012) Cholesterol and triglyceride concentrations in lipoproteins as related to carotid intima–media thickness. Int Heart J 53:29–34CrossRefPubMedGoogle Scholar
  13. 13.
    Simon A, Chironi G, Levenson J (2007) Comparative performance of subclinical atherosclerosis tests in predicting coronary heart disease in asymptomatic individuals. Eur Heart J 28:2967–2971CrossRefPubMedGoogle Scholar
  14. 14.
    O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340:14–22CrossRefPubMedGoogle Scholar
  15. 15.
    Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN (2002) Arterial biology for the investigation of the treatment effects of reducing cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 106:2055–2060CrossRefPubMedGoogle Scholar
  16. 16.
    Crouse JR 3rd, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME, Furberg CD (1995) Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol 75:455–459Google Scholar
  17. 17.
    Beishuizen ED, van de Ree MA, Jukema JW, Tamsma JT, van der Vijver JC, Meinders AE, Putter H, Huisman MV (2004) Two-year statin therapy does not alter the progression of intima-media thickness in patients with type 2 diabetes without manifest cardiovascular disease. Diabetes Care 27:2887–2892CrossRefPubMedGoogle Scholar
  18. 18.
    Crouse JR 3rd, Raichlen JS, Riley WA, Evans GW, Palmer MK, O’Leary DH, Grobbee DE, Bots ML (2007) Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 297:1344–1353CrossRefPubMedGoogle Scholar
  19. 19.
    Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E (2005) Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 46:1405–1410CrossRefPubMedGoogle Scholar
  20. 20.
    Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T (2001) Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 285:1711–1718CrossRefPubMedGoogle Scholar
  21. 21.
    Mercuri M, Bond MG, Sirtori CR, Veglia F, Crepaldi G, Feruglio FS, Descovich G, Ricci G, Rubba P, Mancini M, Gallus G, Bianchi G, D’Alo G, Ventura A (1996) Pravastatin reduces carotid intima–media thickness progression in an asymptomatic hypercholesterolemic mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study. Am J Med 101:627–634CrossRefPubMedGoogle Scholar
  22. 22.
    de Sauvage Nolting PR, de Groot E, Zwinderman AH, Buirma RJ, Trip MD, Kastelein JJ (2003) Regression of carotid and femoral artery intima-media thickness in familial hypercholesterolemia: treatment with simvastatin. Arch Intern Med 163:1837–1841CrossRefPubMedGoogle Scholar
  23. 23.
    Ono K, Kawasaki M, Tanaka R, Segawa T, Matsuo H, Watanabe S, Takemura G, Minatoguchi S (2009) Integrated backscatter and intima-media thickness of the thoracic aorta evaluated by transesophageal echocardiography in hypercholesterolemic patients: effect of pitavastatin therapy. Ultrasound Med Biol 35:193–200CrossRefPubMedGoogle Scholar
  24. 24.
    Amarenco P, Labreuche J, Lavallée P, Touboul PJ (2004) Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 35:2902–2909Google Scholar
  25. 25.
    Yamasaki Y, Kodama M, Nishizawa H, Sakamoto K, Matsuhisa M, Kajimoto Y, Kosugi K, Shimizu Y, Kawamori R, Hori M (2000) Carotid intima–media thickness in Japanese type 2 diabetic subjects: predictors of progression and relationship with incident coronary heart disease. Diabetes Care 23:1310–1315CrossRefPubMedGoogle Scholar
  26. 26.
    Boekholdt SM, Arsenault BJ, Hovingh GK, Mora S, Pedersen TR, Larosa JC, Welch KM, Amarenco P, Demicco DA, Tonkin AM, Sullivan DR, Kirby A, Colhoun HM, Hitman GA, Betteridge DJ, Durrington PN, Clearfield MB, Downs JR, Gotto AM Jr, Ridker PM, Kastelein JJ (2013) Levels and changes of HDL cholesterol and apolipoprotein A–I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation 128:1504–1512CrossRefPubMedGoogle Scholar
  27. 27.
    Kawakami K, Okumura K, Matsui H, Tomida T, Kamiya H, Osanai H, Sakai Y, Kanayama H, Hayakawa T (2001) The apolipoprotein E genotype influences the risk for vasospastic angina. Can J Cardiol 17:660–666PubMedGoogle Scholar
  28. 28.
    Oikawa S, Kita T, Mabuchi H, Matsuzaki M, Matsuzawa Y, Nakaya N, Saito Y, Sasaki J, Shimamoto K, Itakura H (2007) Risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes mellitus on low-dose simvastatin therapy: implication from Japan Lipid Intervention Trial (J-LIT). Atherosclerosis 191:440–446CrossRefPubMedGoogle Scholar
  29. 29.
    Mabuchi H, Kita T, Matsuzaki M, Matsuzawa Y, Nakaya N, Oikawa S, Saito Y, Sasaki J, Shimamoto K, Itakura H (2002) Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease: secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT). Circ J 66:1096–1100CrossRefPubMedGoogle Scholar
  30. 30.
    von Eckardstein A, Rohrer L (2009) Transendothelial lipoprotein transport and regulation of endothelial permeability and integrity by lipoproteins. Curr Opin Lipidol 20:197–205CrossRefGoogle Scholar
  31. 31.
    Ogita M, Miyauchi K, Miyazaki T, Naito R, Konishi H, Tsuboi S, Dohi T, Kasai T, Yokoyama T, Okazaki S, Kurata T, Daida H (2013) Low high-density lipoprotein cholesterol is a residual risk factor associated with long-term clinical outcomes in diabetic patients with stable coronary artery disease who achieve optimal control of low-density lipoprotein cholesterol. Heart Vessels doi: 10.1007/s00380-013-0330-5
  32. 32.
    Cortellaro M, Cofrancesco E, Arbustini E, Rossi F, Negri A, Tremoli E, Gabrielli L, Camera M (2002) Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost 88:41–47PubMedGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  • Kenji Okumura
    • 1
  • Hideto Tsukamoto
    • 1
  • Hideyuki Tsuboi
    • 2
  • Haruo Hirayama
    • 3
  • Haruo Kamiya
    • 4
  • Masato Watarai
    • 5
  • Ryoji Ishiki
    • 6
  • Toyoaki Murohara
    • 7
  • on behalf of the Samurai Study Investigators
  1. 1.Department of CardiologyToki Municipal General HospitalTokiJapan
  2. 2.Department of CardiologyOgaki Municipal HospitalOgakiJapan
  3. 3.Department of CardiologyNagoya Daini Red Cross HospitalNagoyaJapan
  4. 4.Department of CardiologyJapanese Red Cross Nagoya First HospitalNagoyaJapan
  5. 5.Cardiovascular CenterAnjo Kosei HospitalAnjoJapan
  6. 6.Department of Internal MedicineToyota Memorial HospitalToyotaJapan
  7. 7.Department of CardiologyNagoya University Graduate School of MedicineNagoyaJapan

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