Abstract
Purpose
In the last years, the identification of vulnerable atherosclerotic plaques to prevent acute coronary events has been one of the main objectives of the cardiovascular science community. In this review, we provide an overview of vulnerable coronary artery plaque imaging by positron emission tomography (PET).
Methods and results
Relevant methodological and technical aspects of PET on coronary artery plaque imaging are first analysed. Second, the main radiotracers used in this area as well as the main results of the clinical studies published so far are described. From published data, specialized approaches are recommended for imaging protocol and quantitative analysis of plaque activity. 18F-fluorodeoxyglucose (18F-FDG), the first radiotracer used for its wide availability, has several limitations for the detection and quantification of coronary artery plaque inflammation. 18F-sodium fluoride (18F-NaF), a marker of vascular microcalcification, seems to be the most promising radiotracer for vulnerable coronary artery plaque imaging. 68Ga-DOTATATE and 68Ga-pentixafor have also shown interesting results on coronary plaque inflammation in humans. Data on coronary imaging in humans are lacking for other radiotracers that target inflammation, hypoxia and neoangiogenesis.
Conclusions
Molecular imaging by PET is a powerful tool for imaging different components of vulnerable coronary artery plaques and, potentially, for selecting patients at high-risk of myocardial infarction for personalized treatments. However, the results of large clinical trials on asymptomatic patients to link coronary plaque activity to patient outcome are strongly required.
Similar content being viewed by others
References
Roth GA et al (2017) Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 70(1):1–25
Falk E (1983) Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 50(2):127–134
Dickson BC, Gotlieb AI (2003) Towards understanding acute destabilization of vulnerable atherosclerotic plaques. Cardiovasc Pathol 12(5):237–248
Fox JJ, Strauss HW (2009) One step closer to imaging vulnerable plaque in the coronary arteries. J Nucl Med 50(4):497–500
Virmani R et al (2005) Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 25(10):2054–2061
Bentzon JF et al (2014) Mechanisms of plaque formation and rupture. Circ Res 114(12):1852–1866
Wang Y, Vidan E, Bergman GW (1999) Cardiac motion of coronary arteries: variability in the rest period and implications for coronary MR angiography. Radiology 213(3):751–758
Shechter G et al (2004) Respiratory motion of the heart from free breathing coronary angiograms. IEEE Trans Med Imaging 23(8):1046–1056
Joshi NV et al (2014) 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 383(9918):705–713
Rubeaux M et al (2016) Motion correction of 18F-NaF PET for imaging coronary atherosclerotic plaques. J Nucl Med 57(1):54–59
Doris MK et al (2018) Optimization of reconstruction and quantification of motion-corrected coronary PET-CT. J Nucl Cardiol. https://doi.org/10.1007/s12350-018-1317-5
Kwiecinski J et al (2018) Feasibility of coronary (18)F-sodium fluoride positron-emission tomography assessment with the utilization of previously acquired computed tomography angiography. Circ Cardiovasc Imaging 11(12):e008325
Nehmeh SA, Erdi YE (2008) Respiratory motion in positron emission tomography/computed tomography: a review. Semin Nucl Med 38(3):167–176
Buther F et al (2009) List mode-driven cardiac and respiratory gating in PET. J Nucl Med 50(5):674–681
Fayad HJ et al (2013) Generation of 4-dimensional CT images based on 4-dimensional PET-derived motion fields. J Nucl Med 54(4):631–638
Kesner AL et al (2014) On transcending the impasse of respiratory motion correction applications in routine clinical imaging—a consideration of a fully automated data driven motion control framework. EJNMMI Phys 1(1):8
Lassen ML et al (2019) Data-driven gross patient motion detection and compensation: implications for coronary (18)F-NaF PET imaging. J Nucl Med 60(6):830–836
Lamare F et al (2014) Evaluation of respiratory and cardiac motion correction schemes in dual gated PET/CT cardiac imaging. Med Phys 41(7):072504
Hyun MC et al (2017) Technical consideration for dual ECG/respiratory-gated cardiac PET imaging. J Nucl Cardiol 24(4):1246–1252
Virmani R et al (2002) Vulnerable plaque: the pathology of unstable coronary lesions. J Interv Cardiol 15(6):439–446
Otsuka M et al (2008) Quantification of coronary plaque by 64-slice computed tomography: a comparison with quantitative intracoronary ultrasound. Investig Radiol 43(5):314–321
Huet P et al (2015) Variability and uncertainty of 18F-FDG PET imaging protocols for assessing inflammation in atherosclerosis: suggestions for improvement. J Nucl Med 56(4):552–559
Rousset OG, Ma Y, Evans AC (1998) Correction for partial volume effects in PET: principle and validation. J Nucl Med 39(5):904–911
Cal-Gonzalez J et al (2018) Partial volume correction for improved PET quantification in (18)F-NaF imaging of atherosclerotic plaques. J Nucl Cardiol 25(5):1742–1756
Burg S et al (2013) Partial volume effect estimation and correction in the aortic vascular wall in PET imaging. Phys Med Biol 58(21):7527–7542
Yamanouchi M et al (1996) Effect of the duration of fasting on myocardial fluorine-18-fluorodeoxyglucose positron emission tomography images in normal males. Jpn Circ J 60(6):319–327
Wykrzykowska J et al (2009) Imaging of inflamed and vulnerable plaque in coronary arteries with 18F-FDG PET/CT in patients with suppression of myocardial uptake using a low-carbohydrate, high-fat preparation. J Nucl Med 50(4):563–568
Giorgetti A et al (2018) Effect of prolonged fasting and low molecular weight heparin or warfarin therapies on 2-deoxy-2-[18F]-fluoro-d-glucose PET cardiac uptake. J Nucl Cardiol 25(4):1364–1371
Rogers IS et al (2010) Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging 3(4):388–397
Demeure F et al (2014) A randomized trial on the optimization of 18F-FDG myocardial uptake suppression: implications for vulnerable coronary plaque imaging. J Nucl Med 55(10):1629–1635
Cheng VY et al (2012) Coronary arterial 18F-FDG uptake by fusion of PET and coronary CT angiography at sites of percutaneous stenting for acute myocardial infarction and stable coronary artery disease. J Nucl Med 53(4):575–583
Dunphy MP et al (2005) Association of vascular 18F-FDG uptake with vascular calcification. J Nucl Med 46(8):1278–1284
Saam T et al (2010) 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 37(6):1203–1212
Bucerius J et al (2016) Position paper of the Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) on PET imaging of atherosclerosis. Eur J Nucl Med Mol Imaging 43(4):780–792
Bucerius J et al (2014) Optimizing 18F-FDG PET/CT imaging of vessel wall inflammation: the impact of 18F-FDG circulation time, injected dose, uptake parameters, and fasting blood glucose levels. Eur J Nucl Med Mol Imaging 41(2):369–383
Blomberg BA et al (2014) Delayed (1)(8)F-fluorodeoxyglucose PET/CT imaging improves quantitation of atherosclerotic plaque inflammation: results from the CAMONA study. J Nucl Cardiol 21(3):588–597
Menezes LJ et al (2009) Vascular inflammation imaging with 18F-FDG PET/CT: when to image? J Nucl Med 50(6):854–857
Blomberg BA et al (2014) Delayed sodium 18F-fluoride PET/CT imaging does not improve quantification of vascular calcification metabolism: results from the CAMONA study. J Nucl Cardiol 21(2):293–304
Rudd JH et al (2007) (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials. J Am Coll Cardiol 50(9):892–896
Oliveira-Santos M et al (2017) Atherosclerotic plaque metabolism in high cardiovascular risk subjects—a subclinical atherosclerosis imaging study with (18)F-NaF PET-CT. Atherosclerosis 260:41–46
Ferreira MJV et al (2018) Assessment of atherosclerotic plaque calcification using F18-NaF PET-CT. J Nucl Cardiol 25(5):1733–1741
Blomberg BA et al (2015) Impact of personal characteristics and technical factors on quantification of sodium 18F-fluoride uptake in human arteries: prospective evaluation of healthy subjects. J Nucl Med 56(10):1534–1540
Beheshti M et al (2011) Detection and global quantification of cardiovascular molecular calcification by fluoro18-fluoride positron emission tomography/computed tomography–a novel concept. Hell J Nucl Med 14(2):114–120
Blomberg BA et al (2017) Coronary fluorine-18-sodium fluoride uptake is increased in healthy adults with an unfavorable cardiovascular risk profile: results from the CAMONA study. Nucl Med Commun 38(11):1007–1014
Fiz F et al (2016) Correlation between thoracic aorta 18F-natrium fluoride uptake and cardiovascular risk. World J Radiol 8(1):82–89
Matsumoto K et al (2015) Localization of coronary high-intensity signals on T1-weighted MR imaging: relation to plaque morphology and clinical severity of angina pectoris. JACC Cardiovasc Imaging 8(10):1143–1152
Xie Y et al (2017) Coronary atherosclerosis T1-weighed characterization with integrated anatomical reference: comparison with high-risk plaque features detected by invasive coronary imaging. JACC Cardiovasc Imaging 10(6):637–648
Robson PM et al (2017) Coronary artery PET/MR imaging: feasibility, limitations, and solutions. JACC Cardiovasc Imaging 10(10 Pt A):1103–1112
Petibon Y et al (2014) Towards coronary plaque imaging using simultaneous PET-MR: a simulation study. Phys Med Biol 59(5):1203–1222
Tarkin JM, Joshi FR, Rudd JH (2014) PET imaging of inflammation in atherosclerosis. Nat Rev Cardiol 11(8):443–457
Folco EJ et al (2011) Hypoxia but not inflammation augments glucose uptake in human macrophages: implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-d-glucose positron emission tomography. J Am Coll Cardiol 58(6):603–614
Williams G, Kolodny GM (2009) Retrospective study of coronary uptake of 18F-fluorodeoxyglucose in association with calcification and coronary artery disease: a preliminary study. Nucl Med Commun 30(4):287–291
Locorotondo G, Danza ML, Burzotta F, Porto I, Niccoli G, Leone AM et al (2015) Identification of unstable coronary artery plaques by intracoronary optical coherence tomography and positron emission tomography. Eur Heart J. 36(Suppl1):P604
Singh P, Emami H, Subramanian S, Maurovich-Horvat P, Marincheva-Savcheva G, Medina HM et al (2016) Coronary plaque morphology and the anti-Inflammatory impact of atorvastatin: a multicenter 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic study. Circ Cardiovasc Imaging. 9(12):e004195
Nitta Y et al (2013) Pioglitazone decreases coronary artery inflammation in impaired glucose tolerance and diabetes mellitus: evaluation by FDG-PET/CT imaging. JACC Cardiovasc Imaging 6(11):1172–1182
Rominger A et al (2010) In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. J Nucl Med 51(2):193–197
Tarkin JM et al (2017) Detection of Atherosclerotic Inflammation by (68)Ga-DOTATATE PET Compared to [(18)F]FDG PET Imaging. J Am Coll Cardiol 69(14):1774–1791
Mojtahedi A et al (2015) Assessment of vulnerable atherosclerotic and fibrotic plaques in coronary arteries using (68)Ga-DOTATATE PET/CT. Am J Nucl Med Mol Imaging 5(1):65–71
Aikawa E et al (2007) Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 116(24):2841–2850
Vengrenyuk Y et al (2006) A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci USA 103(40):14678–14683
Irkle A et al (2015) Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun 6:7495
Creager MD et al (2019) (18)F-fluoride signal amplification identifies microcalcifications associated with atherosclerotic plaque instability in positron emission tomography/computed tomography images. Circ Cardiovasc Imaging 12(1):e007835
Derlin T et al (2010) Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med 51(6):862–865
Dweck MR et al (2012) Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol 59(17):1539–1548
Kitagawa T et al (2017) (18)F-sodium fluoride positron emission tomography for molecular imaging of coronary atherosclerosis based on computed tomography analysis. Atherosclerosis 263:385–392
Lee JM, Bang JI, Koo BK, Hwang D, Park J, Zhang J et al (2017) Clinical relevance of (18)F-sodium fluoride positron-emission tomography in noninvasive identification of high-risk plaque in patients with coronary artery disease. Circ Cardiovasc Imaging. 10(11):e006704. https://doi.org/10.1161/CIRCIMAGING.117.006704
Li L et al (2018) Sodium-fluoride PET-CT for the non-invasive evaluation of coronary plaques in symptomatic patients with coronary artery disease: a cross-correlation study with intravascular ultrasound. Eur J Nucl Med Mol Imaging 45(12):2181–2189
Kitagawa T et al (2018) Predictive value of (18)F-Sodium fluoride positron emission tomography in detecting high-risk coronary artery disease in combination with computed tomography. J Am Heart Assoc 7(20):e010224
Vöö S, Kwee RM, Sluimer JC, Schreuder FH, Wierts R, Bauwens M, Heeneman S, Cleutjens JP, van Oostenbrugge RJ, Daemen JW, Daemen MJ, Mottaghy FM, Kooi ME (2016) Imaging intraplaque inflammation in carotid atherosclerosis with 18F-fluorocholine positron emission tomography-computed tomography: prospective study on vulnerable atheroma with immunohistochemical validation. Circ Cardiovasc Imaging. 9(5):e004467. https://doi.org/10.1161/CIRCIMAGING.115.004467
Kato K et al (2009) Evaluation and comparison of 11C-choline uptake and calcification in aortic and common carotid arterial walls with combined PET/CT. Eur J Nucl Med Mol Imaging 36(10):1622–1628
Gaemperli O et al (2012) Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. Eur Heart J 33(15):1902–1910
Mateo J et al (2014) Noninvasive assessment of hypoxia in rabbit advanced atherosclerosis using (1)(8)F-fluoromisonidazole positron emission tomographic imaging. Circ Cardiovasc Imaging 7(2):312–320
Nie X et al (2016) Imaging of hypoxia in mouse atherosclerotic plaques with (64)Cu-ATSM. Nucl Med Biol 43(9):534–542
Beer AJ et al (2014) PET/CT imaging of integrin alphavbeta3 expression in human carotid atherosclerosis. JACC Cardiovasc Imaging 7(2):178–187
Wester HJ et al (2015) Disclosing the CXCR75 expression in lymphoproliferative diseases by targeted molecular imaging. Theranostics 5(6):618–630
Derlin T et al (2018) Imaging of chemokine receptor CXCR76 expression in culprit and nonculprit coronary atherosclerotic plaque using motion-corrected [(68)Ga]pentixafor PET/CT. Eur J Nucl Med Mol Imaging 45(11):1934–1944
Tawakol A et al (2017) Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet 389(10071):834–845
Corriveau RA et al (2016) The science of vascular contributions to cognitive impairment and dementia (VCID): a framework for advancing research priorities in the cerebrovascular biology of cognitive decline. Cell Mol Neurobiol 36(2):281–288
Dweck MR et al (2013) Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation? Eur Heart J 34(21):1567–1574
Arbab-Zadeh A, Fuster V (2015) The myth of the “vulnerable plaque”: transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J Am Coll Cardiol 65(8):846–855
Li Y et al (2012) Association of vascular fluoride uptake with vascular calcification and coronary artery disease. Nucl Med Commun 33(1):14–20
Cal-Gonzalez J et al (2017) Impact of motion compensation and partial volume correction for (18)F-NaF PET/CT imaging of coronary plaque. Phys Med Biol 63(1):015005
Marchesseau S et al (2018) Hybrid PET/CT and PET/MRI imaging of vulnerable coronary plaque and myocardial scar tissue in acute myocardial infarction. J Nucl Cardiol 25(6):2001–2011
Moghbel M et al (2018) The role of PET in evaluating atherosclerosis: a critical review. Semin Nucl Med 48(6):488–497
Author information
Authors and Affiliations
Contributions
LL: conception and design of the article, literature search and analysis, drafting of the article, and critical revision. PN: literature search and analysis and manuscript writing. CC: literature search and analysis, and manuscript writing. IL: literature search and analysis, manuscript writing, and critical revision. AG: design of the article, manuscript writing and critical revision. All authors approved the final version of the article.
Corresponding author
Ethics declarations
Conflict of interest
All authors declare that there is no conflict of interest regarding the publication of this article.
Ethical standards
This article does not contain any studies with human or animal subjects performed by the any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Leccisotti, L., Nicoletti, P., Cappiello, C. et al. PET imaging of vulnerable coronary artery plaques. Clin Transl Imaging 7, 267–284 (2019). https://doi.org/10.1007/s40336-019-00334-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40336-019-00334-3