Predictors of change in carotid atherosclerotic plaque inflammation and burden as measured by 18-FDG-PET and MRI, respectively, in the dal-PLAQUE study
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Baseline predictors of response to treatment of patients with coronary heart disease (CHD) with respect to vascular inflammation and atherosclerotic plaque burden are poorly understood. From post hoc analysis of the dal-PLAQUE study (NCT00655473), 18F-fluorodeoxyglucose-positron emission tomography (18-FDG-PET) imaging and carotid black blood magnetic resonance imaging (MRI) were used to track changes in these vascular parameters. Baseline demographics, imaging, and biomarkers were collected/measured in 130 patients with CHD or CHD risk-equivalents, and imaging follow-up at 6 months (PET) and 24 months (MRI) was performed. Using stepwise linear regression, predictors of change in carotid plaque inflammation by PET [target-to-background ratio (TBR), n = 92] and plaque burden by MRI [wall area (WA) and total vessel area (TVA), n = 89] were determined. Variables with p < 0.05 in multivariable models were considered independently significant. Interleukin-6, systolic blood pressure and standard deviation of wall thickness (WT) at baseline were independently positively associated with 18-FDG uptake (mean of maximum [MeanMax] TBR change over 6 months). Mean of mean TBR, phospholipase A2, apolipoprotein A-I, and high-sensitivity C-reactive protein at baseline were independently negatively associated with MeanMax TBR change over 6 months. Mean WT and plasminogen activator inhibitor-1 (PAI-1) activity at baseline, and age, were independently associated with change in WA over 24 months. For TVA changes; mean WA and PAI-1 activity at baseline, age, and female gender were independent predictors. These findings may help determine patients most suitable for clinical trials employing plaque inflammation or burden changes as endpoints.
KeywordsFluorodeoxyglucose-positron emission tomography Inflammation Magnetic resonance imaging Plaque burden
The authors thank Michael E. Farkouh and Valentin Fuster for their review and feedback of the manuscript. This study was funded by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Prime Healthcare during the preparation of this report, and funded by F. Hoffmann-La Roche Ltd. All opinions expressed are those of the authors.
Conflict of interest
V.M., J.B. and D.S. indicate they have nothing to disclose. M.W. discloses that he has received honoraria from Roche. A.T. discloses that he has received honoraria from Roche, BMS and Novartis, and research grants from Merck, BMS, Genentech, GSK and VBL. D.K. was an employee of F. Hoffman-La Roche Ltd at the time the study was performed. M.A. is an employee of F. Hoffman-La Roche Ltd and receives share options. J.H.F.R. discloses that he has received honoraria from Roche and is part-supported by the National Institute for Health Research Cambridge Biomedical Research Centre. Z.A.F. discloses that he has received research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb, and Via Pharmaceuticals and honoraria from Roche.
- 5.Fryburg DA, Vassileva MT (2011) Atherosclerosis drug development in jeopardy: the need for predictive biomarkers of treatment response. Sci Transl Med 3(72):1–5Google Scholar
- 6.Fayad ZA, Mani V, Woodward M, Kallend D, Bansilal S, Pozza J, Burgess T, Fuster V, Rudd JH, Tawakol A, Farkouh ME (2011) Rationale and design of dal-PLAQUE: a study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Am Heart J 162(2):214–221Google Scholar
- 7.Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, Johnström P, Davenport AP, Kirkpatrick PJ, Arch BN, Pickard JD, Weissberg PL (2002) Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 105:2708–2711PubMedCrossRefGoogle Scholar
- 9.Mizoguchi M, Tahara N, Tahara A, Nitta Y, Kodama N, Oba T, Mawatari K, Yasukawa H, Kaida H, Ishibashi M, Hayabuchi N, Harada H, Ikeda H, Yamagishi S, Imaizumi T (2011) Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging 4:1110–1118PubMedCrossRefGoogle Scholar
- 13.Corti R, Fuster V (2011) Imaging of atherosclerosis: magnetic resonance imaging. Eur Heart J 32(14):1709–1719Google Scholar
- 14.Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, Fuster V, Ballantyne CM, Stein EA, Tardif JC, Rudd JH, Farkouh ME, Tawakol A, dal-PLAQUE Investigators (2011) Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 378:1547–1559PubMedCrossRefGoogle Scholar
- 16.Rudd JH, Myers KS, Bansilal S, Machac J, Pinto CA, Tong C, Rafique A, Hargeaves R, Farkouh M, Fuster V, Fayad ZA (2008) Atherosclerosis inflammation imaging with 18F-FDG PET: carotid, iliac, and femoral uptake reproducibility, quantification methods, and recommendations. J Nucl Med 49:871–878PubMedCrossRefGoogle Scholar
- 17.El Aidi H, Mani V, Weinshelbaum KB, Aguiar SH, Taniguchi H, Postley JE, Samber DD, Cohen EI, Stern J, van der Geest RJ, Reiber JH, Woodward M, Fuster V, Gidding SS, Fayad ZA (2009) Cross-sectional, prospective study of MRI reproducibility in the assessment of plaque burden of the carotid arteries and aorta. Nat Clin Pract Cardiovasc Med 6:219–228PubMedCrossRefGoogle Scholar
- 19.Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M, FIELD study investigators (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849–1861PubMedCrossRefGoogle Scholar
- 20.Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS, dal-OUTCOMES Investigators (2012) Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 367:2089–2099PubMedCrossRefGoogle Scholar
- 22.Mani V, Muntner P, Gidding SS, Aguiar SH, El Aidi H, Weinshelbaum KB, Taniguchi H, van der Geest R, Reiber JH, Bansilal S, Farkouh M, Fuster V, Postley JE, Woodward M, Fayad ZA (2009) Cardiovascular magnetic resonance parameters of atherosclerotic plaque burden improve discrimination of prior major adverse cardiovascular events. J Cardiovasc Magn Reson 11:10PubMedCentralPubMedCrossRefGoogle Scholar
- 23.Bucerius J, Duivenvoorden R, Mani V, Moncrieff C, Rudd JH, Calcagno C, Machac J, Fuster V, Farkouh ME, Fayad ZA (2011) Prevalence and risk factors of carotid vessel wall inflammation in coronary artery disease patients: FDG-PET and CT imaging study. JACC Cardiovasc Imaging 4:1195–1205PubMedCrossRefGoogle Scholar
- 29.Gonçalves I, Edsfeldt A, Ko NY, Grufman H, Berg K, Björkbacka H, Nitulescu M, Persson A, Nilsson M, Prehn C, Adamski J, Nilsson J (2012) Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. Arterioscler Thromb Vasc Biol 32:1505–1512PubMedCrossRefGoogle Scholar
- 31.Raiko JR, Oikonen M, Wendelin-Saarenhovi M, Siitonen N, Kähönen M, Lehtimäki T, Viikari J, Jula A, Loo BM, Huupponen R, Saarikoski L, Juonala M, Raitakari OT (2012) Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study. Atherosclerosis 224:208–212PubMedCrossRefGoogle Scholar