[ 1 8 F ] - F l u o ro d e o x y g l u c o s e PE T Imaging of A t h e ros c l e ros i s Björn A. Blomberg, MD, MSca,b, Poul Flemming Høilund-Carlsen, MD, DMSca,* KEYWORDS
18
F-fluorodeoxyglucose PET Atherosclerosis Arterial inflammation
KEY POINTS [18F]-fluorodeoxyglucose PET (18FDG PET) imaging can assess atherosclerosis by targeting atherosclerotic plaque glycolysis, a surrogate marker of plaque inflammation and hypoxia. Arterial 18FDG PET is reliable and reproducible, with excellent inter-rater, intrarater, and inter-scan agreement; hence, 18FDG PET can be utilized as a surrogate end point in clinical drug trials, improving trial efficiency. Retrospective data suggest that 18FDG PET provides prognostic information above traditional cardiovascular risk factors, the Framingham risk score, and the coronary calcium score. Combined with other imaging modalities, 18FDG PET can help elucidate pathophysiologic mechanisms of atherosclerosis.
Atherosclerosis is a disease of the arteries characterized by deposition of plaques on their inner walls. These plaques contain contain lipids, macrophages, and other types of inflammatory cells.1 Triggered by cardiovascular risk factors and numerous proinflammatory mediators, atherosclerotic plaques mature, grow, and, by yet to be fully understood mechanisms, become vulnerable for rupture.2 Rupture of the vulnerable plaque is considered the single-most frequent cause of acute cardiovascular events, such as myocardial infarction and stroke.3,4 An optimal strategy to reduce cardiovascular morbidity and mortality would be to identify asymptomatic patients with rupture-prone plaques.5,6 In theory, patients with rupture-prone plaques benefit most from intensive evidence-based medical interventions. Currently, the degree of
luminal stenosis identifies patients with vulnerable plaques. In line with this paradigm, nuclear cardiology has focused on evaluating hemodynamic consequences of arterial stenosis.7 As an offshoot of this, [18F]-fluorodeoxyglucose PET (18FDG PET) imaging addressed the phenomenon of myocardial viability. Patients with large perfusion defects but with retained myocardial glucose metabolism were found in varying degrees to benefit hemodynamically from revascularization procedures, even if traditional myocardial perfusion imaging had revealed fixed or conceivably irreversible, perfusion defects.8 Nonetheless, angiographic and pathologic studies showed that most acute cardiovascular events occur in patients without marked stenosis, and it has become increasingly clear that the degree of plaque inflammation, rather than arterial stenosis, predicts plaque vulnerability.9–12
Disclosures: The authors have nothing to disclose. a Department of Nuclear Medicine, Odense University Hospital, Søndre Boulevard 29, 5000 Odense, Denmark; b Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands * Corresponding author. E-mail address: [email protected] PET Clin 10 (2015) 1–7 http://dx.doi.org/10.1016/j.cpet.2014.09.001 1556-8598/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
pet.theclinics.com
INTRODUCTION
2
Blomberg & Høilund-Carlsen Because 18FDG PET can accurately detect inflammation, it is believed that 18FDG PET could play an important role in identifying patients with rupture-prone plaques. Evidence in favor of this hypothesis was first provided at the turn of the 21st century. In 2001, a retrospective study demonstrated that half of patients referred for 18 FDG PET had evidence of 18FDG retention in various parts of the arterial tree.13 It was suggested that arterial 18FDG uptake could be associated with the accumulation and activity level of macrophages present in atherosclerotic plaque. Subsequent studies confirmed this suggestion by demonstrating that 18FDG cumulates in plaque macrophages and that uptake strongly correlates with macrophage density.14–19 This was an important observation, mainly because macrophages play a pivotal role in plaque initiation, progression, and inception of plaque vulnerability.20 In addition, arterial 18FDG retention seems to depend on plaque hypoxia,21 another determinant associated with plaque vulnerability and rupture. Therefore, by targeting plaque macrophages and hypoxia, 18 FDG PET can potentially detect atherosclerosis, quantitate its degree, evaluate response to treatment, and prognosticate risk for acute cardiovascular events.
RELATION WITH CARDIOVASCULAR RISK AND CARDIOVASCULAR RISK FACTORS Both retrospective and prospective studies demonstrated positive correlations between arterial 18FDG avidity and traditional cardiovascular risk factors, such as aging,13,22,23 hypercholesterolemia,22 hypertension,24 metabolic syndrome,25 type 2 diabetes mellitus,26,27 smoking,22,23 obesity,23,27 and inflammatory biomarkers.28 Other studies showed positive correlations between arterial FDG uptake and cardiovascular events.14,29–33 Recently, a retrospective study in 513 patients demonstrated that aortic 18FDG avidity predicted cardiovascular events, independent of traditional cardiovascular risk factors and the coronary calcium score.34 Adding the aortic 18FDG retention index to the Framingham risk score resulted in a net reclassification improvement of approximately 25% compared with the Framingham risk score alone. In addition, aortic 18FDG uptake was inversely associated with the timing of cardiovascular events. These data suggest that arterial 18FDG uptake is helpful in risk stratification of patients at risk for cardiovascular disease, beyond standard tools, such as the Framingham risk score and coronary calcium score. Furthermore, identifying high-risk asymptomatic patients can guide treatment interventions (Figs. 1–3).
TREATMENT EVALUATION As a marker of atherosclerotic plaque inflammation, arterial 18FDG avidity can evaluate the effect of antiatherosclerotic drugs. Several studies have demonstrated that arterial 18FDG activity could be reduced in patients treated with lipid-lowering medication, antidiabetic drugs, and life-style interventions at 3 to 6 months of follow-up.35–38 A recently published randomized trial investigated whether high-dose statin treatment would attenuate arterial 18FDG activity more than low-dose statin treatment.39 To this end, 76 patients with established atherosclerosis were randomized to receive either daily 10 mg or 80 mg of atorvastatin. Treatment effects were assessed with 18FDG PET/ CT at baseline and at 4 and 12 weeks follow-up. At 4 weeks, arterial 18FDG activity was significantly reduced compared with baseline for both the 10 mg and 80 mg groups. At 12 weeks, an additional relative reduction was observed for the 80 mg group only, suggesting a dose–response relationship between statin therapy and reduction of arterial 18FDG activity. In addition to statins, several other drugs aimed at attenuating atherosclerosis have been evaluated with 18FDG PET. However, both vitamin B therapy and rilapladib, an inhibitor of lipoprotein-associated phospholipase A2, seem to be ineffective in attenuating the arterial 18FDG signal.40,41
PATHOPHYSIOLOGY In addition to risk stratification and treatment evaluation, assessment of plaque biology is another major domain for 18FDG PET imaging of atherosclerosis. Studies investigating inflammation (18FDG uptake), arterial mineral deposition (Na18F uptake), and vascular calcification, as seen on CT, have shown that these entities can vary among different parts of the arterial tree.42–44 It has been suggested that each marker represents distinct phases of atheroma formation. Recently, this theory found support in a retrospective longitudinal 18FDG PET/CT study.45 In 137 patients who underwent serial 18FDG PET/ CT examinations, baseline arterial 18FDG retention significantly related to subsequent vascular calcification at follow-up, even after adjustment for traditional cardiovascular risk factors. These data suggest that vascular calcification, a marker of plaque progression, seems to be preceded by vascular inflammation. Therefore, it seems that 18 FDG PET combined with Na18F PET and CT can play a synergistic role in assessment of atherosclerotic disease progression and potentially plaque and patient vulnerability.
PET Imaging of Atherosclerosis
Fig. 1. Maximum-intensity projection PET images acquired 3 hours after administration of approximately 4 MBq of 18FDG per kilogram of body weight. (A) 25-year-old man without traditional cardiovascular risk factors. Uptake of 18FDG was absent in the arterial system. (B) 66-year-old man with hypertension, hypercholesterolemia, and extensive retention of 18FDG in the femoral/popliteal arteries (black arrowheads) and subclavian/brachial arteries (white arrowheads).
LIMITATIONS 18 FDG PET imaging of atherosclerosis has several limitations. Foremost, 18FDG uptake is not specific for atherosclerosis. Therefore, detecting arterial
18
FDG uptake next to other 18FDG avid structures can be challenging. This is particularly problematic when imaging the coronary arteries, generally regarded as the culprit artery in patients suffering
Fig. 2. Axial CT (A) and fused 18FDG PET/CT (B) images of a 36-year-old man demonstrating 18FDG accumulation in the right carotid artery (white arrowhead) and left carotid artery (black arrowhead).
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Blomberg & Høilund-Carlsen
Fig. 3. Axial CT (A) and fused 18FDG PET/CT (B) images of a 36-year-old man demonstrating 18FDG accumulation in the ascending aorta (white arrowheads) and descending aorta (black arrowhead).
Fig. 4. Axial CT (A) and fused 18FDG PET/CT (B) images of a 37-year-old woman showing the heart at the level of the left main coronary artery. Uptake of 18FDG in the myocardium was low. Therefore, 18FDG accumulation was detectable in the left main (black arrowhead), left circumflex (black arrow), and left anterior descending coronary artery (white arrow). Furthermore, 18FDG retention was observed in the ascending and descending aorta (white arrowheads).
Box 1 Suggestions for an imaging protocol The recommended time between The recommended
18
FDG administration and PET acquisition is 180 minutes.53,54
18
FDG dosage lies between 185 and 300 MBq.55
A blood glucose level less than 7.0 mmol/L (w126 mg/dL) is advised.55 At 180 minutes, the recommended acquisition time per bed position is 3.5 minutes. PET image reconstruction should take attenuation, scatter, random coincidences, and scanner dead time into account. Attenuation-corrected PET images are acquired by coregistration of a whole-body low-dose CT image (140 kV tube voltage, 30–110 mA tube current, 0.8 s gantry rotation time, slice thickness 3.75 mm). The estimated effective radiation dosage per whole-body
18
FDG PET/CT is approximately 7 mSv.
PET Imaging of Atherosclerosis from a myocardial infarction. High myocardial 18 FDG retention and cardiac motion artifacts prevent accurate detection of coronary 18FDG uptake. However, imaging the coronary arteries is possible in conditions in which myocardial glucose metabolism is low, such as after fasting or dietary preparation (Fig. 4). Nonetheless, coronary 18FDG PET imaging with dietary preparation has been applied with varying succes.46–49 Other obstacles hampering atherosclerosis imaging with 18FDG PET are a lack of standardized and validated imaging protocols. Box 1 proposes an 18FDG PET/CT imaging protocol optimized for atherosclerosis imaging. Also in need of standardization and validation are quantification methodologies.50
SUMMARY Initial results represent important first steps in determining the feasibility and clinical benefit of 18 FDG PET imaging for early atherosclerotic disease. Prospective long-term follow-up studies are now needed to assess the risk stratification capabilities of 18FDG PET compared with currently established methods, such the Framingham risk score, the coronary calcium score, and other imaging modalities. Similarly, treatment evaluation studies require large randomized controlled trials. Other obstacles that require attention include standardization and validation of imaging and quantification protocols.51,52
REFERENCES 1. Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17:1410–22. 2. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004–13. 3. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352: 1685–95. 4. Kolodgie FD, Burke AP, Farb A, et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol 2001;16:285–92. 5. Greenland P, Abrams J, Aurigemma GP, et al. Prevention Conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden: Writing Group III. Circulation 2000;101:E16–22. 6. Taylor AJ, Merz CN, Udelson JE. 34th Bethesda Conference: executive summary—can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease? J Am Coll Cardiol 2003;41:1860–2.
7. Jaarsma C, Leiner T, Bekkers SC, et al. Diagnostic performance of noninvasive myocardial perfusion imaging using single-photon emission computed tomography, cardiac magnetic resonance, and positron emission tomography imaging for the detection of obstructive coronary artery disease: a meta-analysis. J Am Coll Cardiol 2012;59:1719–28. 8. Camici PG, Prasad SK, Rimoldi OE. Stunning, hibernation, and assessment of myocardial viability. Circulation 2008;117:103–14. 9. Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12:56–62. 10. Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988;9: 1317–23. 11. Pasterkamp G, Schoneveld AH, van der Wal AC, et al. Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol 1998; 32:655–62. 12. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 2003;108:1772–8. 13. Yun M, Yeh D, Araujo LI, et al. F-18 FDG uptake in the large arteries: a new observation. Clin Nucl Med 2001;26:314–9. 14. Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]fluorodeoxyglucose positron emission tomography. Circulation 2002;105:2708–11. 15. Tawakol A, Migrino RQ, Bashian GG, 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. 16. Menezes LJ, Kotze CW, Agu O, et al. Investigating vulnerable atheroma using combined (18)F-FDG PET/CT angiography of carotid plaque with immunohistochemical validation. J Nucl Med 2011;52: 1698–703. 17. Figueroa AL, Subramanian SS, Cury RC, et al. Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features: a comparison between positron emission tomography activity, plaque morphology, and histopathology. Circ Cardiovasc Imaging 2012;5:69–77. 18. Masteling MG, Zeebregts CJ, Tio RA, et al. High-resolution imaging of human atherosclerotic carotid plaques with micro 18F-FDG PET scanning exploring plaque vulnerability. J Nucl Cardiol 2011; 18:1066–75. 19. Graebe M, Pedersen SF, Borgwardt L, et al. Molecular pathology in vulnerable carotid plaques: correlation
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with [18]-fluorodeoxyglucose positron emission tomography (FDG-PET). Eur J Vasc Endovasc Surg 2009;37:714–21. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011;145:341–55. Folco EJ, Sheikine Y, Rocha VZ, et al. 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 2011;58:603–14. Yun M, Jang S, Cucchiara A, et al. 18F FDG uptake in the large arteries: a correlation study with the atherogenic risk factors. Semin Nucl Med 2002;32:70–6. Bucerius J, Duivenvoorden R, Mani V, et al. Prevalence and risk factors of carotid vessel wall inflammation in coronary artery disease patients: FDG-PET and CT imaging study. JACC Cardiovasc Imaging 2011;4:1195–205. Tatsumi M, Cohade C, Nakamoto Y, et al. Fluorodeoxyglucose uptake in the aortic wall at PET/CT: possible finding for active atherosclerosis. Radiology 2003;229:831–7. Tahara N, Kai H, Yamagishi S, 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. Kim TN, Kim S, Yang SJ, 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. Bucerius J, Mani V, Moncrieff C, et al. Impact of noninsulin-dependent type 2 diabetes on carotid wall 18F-fluorodeoxyglucose positron emission tomography uptake. J Am Coll Cardiol 2012;59: 2080–8. Duivenvoorden R, Mani V, Woodward M, et al. Relationship of serum inflammatory biomarkers with plaque inflammation assessed by FDG PET/CT: the dal-PLAQUE study. JACC Cardiovasc Imaging 2013;6:1087–94. Arauz A, Hoyos L, Zenteno M, et al. Carotid plaque inflammation detected by 18F-fluorodeoxyglucosepositron emission tomography. Pilot study. Clin Neurol Neurosurg 2007;109:409–12. Davies JR, Rudd JH, Fryer TD, et al. Identification of culprit lesions after transient ischemic attack by combined 18F fluorodeoxyglucose positron-emission tomography and high-resolution magnetic resonance imaging. Stroke 2005;36:2642–7. Grandpierre S, Desandes E, Meneroux B, 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.
32. Paulmier B, Duet M, Khayat R, 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. 33. Rominger A, Saam T, Wolpers 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. 34. Figueroa AL, Abdelbaky A, Truong QA, et al. Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events. JACC Cardiovasc Imaging 2013;6:1250–9. 35. Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006;48:1825–31. 36. Ishii H, Nishio M, Takahashi H, et al. Comparison of atorvastatin 5 and 20 mg/d for reducing F-18 fluorodeoxyglucose uptake in atherosclerotic plaques on positron emission tomography/computed tomography: a randomized, investigator-blinded, open-label, 6-month study in Japanese adults scheduled for percutaneous coronary intervention. Clin Ther 2010;32:2337–47. 37. Lee SJ, On YK, Lee EJ, et al. Reversal of vascular 18F-FDG uptake with plasma high-density lipoprotein elevation by atherogenic risk reduction. J Nucl Med 2008;49:1277–82. 38. Duivenvoorden R, Fayad ZA. Utility of atherosclerosis imaging in the evaluation of high-density lipoprotein-raising therapies. Curr Atheroscler Rep 2011;13:277–84. 39. Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/ computed tomography feasibility study. J Am Coll Cardiol 2013;62:909–17. 40. Potter K, Lenzo N, Eikelboom JW, et al. Effect of long-term homocysteine reduction with B vitamins on arterial wall inflammation assessed by fluorodeoxyglucose positron emission tomography: a randomised double-blind, placebo-controlled trial. Cerebrovasc Dis 2009;27:259–65. 41. Tawakol A, Singh P, Rudd JH, et al. Effect of treatment for 12 weeks with rilapladib, a lipoproteinassociated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-positron emission tomography imaging. J Am Coll Cardiol 2014;63:86–8. 42. Derlin T, Toth Z, Papp L, et al. Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study. J Nucl Med 2011;52:1020–7. 43. Beheshti M, Saboury B, Mehta NN, et al. Detection and global quantification of cardiovascular
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molecular calcification by fluoro18-fluoride positron emission tomography/computed tomography—a novel concept. Hell J Nucl Med 2011;14:114–20. Dweck MR, Chow MW, Joshi NV, et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol 2012;59: 1539–48. Abdelbaky A, Corsini E, Figueroa AL, et al. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDGPET/CT study. Circ Cardiovasc Imaging 2013;6: 747–54. Cheng VY, Slomka PJ, Le Meunier L, et al. Coronary arterial 18F-FDG uptake by fusion of PETand coronary CT angiography at sites of percutaneous stenting for acute myocardial infarction and stable coronary artery disease. J Nucl Med 2012;53:575–83. Joshi NV, Vesey AT, Williams MC, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 2014;383: 705–13. Rogers IS, Nasir K, Figueroa AL, et al. Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging 2010;3:388–97. Wykrzykowska J, Lehman S, Williams G, et al. Imaging of inflamed and vulnerable plaque in coronary arteries with 18F-FDG PET/CT in patients with
50.
51.
52.
53.
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suppression of myocardial uptake using a lowcarbohydrate, high-fat preparation. J Nucl Med 2009;50:563–8. Sadeghi MM. F-FDG PET and vascular inflammation: time to refine the paradigm? J Nucl Cardiol 2014. http://dx.doi.org/10.1007/s12350-014-9917-1, in press. Sheikine Y, Akram K. FDG-PET imaging of atherosclerosis: do we know what we see? Atherosclerosis 2010;211:371–80. Cocker MS, Mc Ardle B, Spence JD, et al. Imaging atherosclerosis with hybrid [18F]fluorodeoxyglucose positron emission tomography/computed tomography imaging: what Leonardo da Vinci could not see. J Nucl Cardiol 2012;19:1211–25. Blomberg BA, Akers SR, Saboury B, et al. Delayed time-point 18F-FDG PET CT imaging enhances assessment of atherosclerotic plaque inflammation. Nucl Med Commun 2013;34:860–7. Blomberg BA, Thomassen A, Takx RA, et al. Delayed (1)(8)F-fluorodeoxyglucose PET/CT imaging improves quantitation of atherosclerotic plaque inflammation: results from the CAMONA study. J Nucl Cardiol 2014;21:588–97. Bucerius J, Mani V, Moncrieff C, et al. 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 2014; 41:369–83.
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18
F-fluorodeoxyglucose PET Atherosclerosis Arterial inflammation
KEY POINTS [18F]-fluorodeoxyglucose PET (18FDG PET) imaging can assess atherosclerosis by targeting atherosclerotic plaque glycolysis, a surrogate marker of plaque inflammation and hypoxia. Arterial 18FDG PET is reliable and reproducible, with excellent inter-rater, intrarater, and inter-scan agreement; hence, 18FDG PET can be utilized as a surrogate end point in clinical drug trials, improving trial efficiency. Retrospective data suggest that 18FDG PET provides prognostic information above traditional cardiovascular risk factors, the Framingham risk score, and the coronary calcium score. Combined with other imaging modalities, 18FDG PET can help elucidate pathophysiologic mechanisms of atherosclerosis.
Atherosclerosis is a disease of the arteries characterized by deposition of plaques on their inner walls. These plaques contain contain lipids, macrophages, and other types of inflammatory cells.1 Triggered by cardiovascular risk factors and numerous proinflammatory mediators, atherosclerotic plaques mature, grow, and, by yet to be fully understood mechanisms, become vulnerable for rupture.2 Rupture of the vulnerable plaque is considered the single-most frequent cause of acute cardiovascular events, such as myocardial infarction and stroke.3,4 An optimal strategy to reduce cardiovascular morbidity and mortality would be to identify asymptomatic patients with rupture-prone plaques.5,6 In theory, patients with rupture-prone plaques benefit most from intensive evidence-based medical interventions. Currently, the degree of
luminal stenosis identifies patients with vulnerable plaques. In line with this paradigm, nuclear cardiology has focused on evaluating hemodynamic consequences of arterial stenosis.7 As an offshoot of this, [18F]-fluorodeoxyglucose PET (18FDG PET) imaging addressed the phenomenon of myocardial viability. Patients with large perfusion defects but with retained myocardial glucose metabolism were found in varying degrees to benefit hemodynamically from revascularization procedures, even if traditional myocardial perfusion imaging had revealed fixed or conceivably irreversible, perfusion defects.8 Nonetheless, angiographic and pathologic studies showed that most acute cardiovascular events occur in patients without marked stenosis, and it has become increasingly clear that the degree of plaque inflammation, rather than arterial stenosis, predicts plaque vulnerability.9–12
Disclosures: The authors have nothing to disclose. a Department of Nuclear Medicine, Odense University Hospital, Søndre Boulevard 29, 5000 Odense, Denmark; b Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands * Corresponding author. E-mail address: [email protected] PET Clin 10 (2015) 1–7 http://dx.doi.org/10.1016/j.cpet.2014.09.001 1556-8598/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
pet.theclinics.com
INTRODUCTION
2
Blomberg & Høilund-Carlsen Because 18FDG PET can accurately detect inflammation, it is believed that 18FDG PET could play an important role in identifying patients with rupture-prone plaques. Evidence in favor of this hypothesis was first provided at the turn of the 21st century. In 2001, a retrospective study demonstrated that half of patients referred for 18 FDG PET had evidence of 18FDG retention in various parts of the arterial tree.13 It was suggested that arterial 18FDG uptake could be associated with the accumulation and activity level of macrophages present in atherosclerotic plaque. Subsequent studies confirmed this suggestion by demonstrating that 18FDG cumulates in plaque macrophages and that uptake strongly correlates with macrophage density.14–19 This was an important observation, mainly because macrophages play a pivotal role in plaque initiation, progression, and inception of plaque vulnerability.20 In addition, arterial 18FDG retention seems to depend on plaque hypoxia,21 another determinant associated with plaque vulnerability and rupture. Therefore, by targeting plaque macrophages and hypoxia, 18 FDG PET can potentially detect atherosclerosis, quantitate its degree, evaluate response to treatment, and prognosticate risk for acute cardiovascular events.
RELATION WITH CARDIOVASCULAR RISK AND CARDIOVASCULAR RISK FACTORS Both retrospective and prospective studies demonstrated positive correlations between arterial 18FDG avidity and traditional cardiovascular risk factors, such as aging,13,22,23 hypercholesterolemia,22 hypertension,24 metabolic syndrome,25 type 2 diabetes mellitus,26,27 smoking,22,23 obesity,23,27 and inflammatory biomarkers.28 Other studies showed positive correlations between arterial FDG uptake and cardiovascular events.14,29–33 Recently, a retrospective study in 513 patients demonstrated that aortic 18FDG avidity predicted cardiovascular events, independent of traditional cardiovascular risk factors and the coronary calcium score.34 Adding the aortic 18FDG retention index to the Framingham risk score resulted in a net reclassification improvement of approximately 25% compared with the Framingham risk score alone. In addition, aortic 18FDG uptake was inversely associated with the timing of cardiovascular events. These data suggest that arterial 18FDG uptake is helpful in risk stratification of patients at risk for cardiovascular disease, beyond standard tools, such as the Framingham risk score and coronary calcium score. Furthermore, identifying high-risk asymptomatic patients can guide treatment interventions (Figs. 1–3).
TREATMENT EVALUATION As a marker of atherosclerotic plaque inflammation, arterial 18FDG avidity can evaluate the effect of antiatherosclerotic drugs. Several studies have demonstrated that arterial 18FDG activity could be reduced in patients treated with lipid-lowering medication, antidiabetic drugs, and life-style interventions at 3 to 6 months of follow-up.35–38 A recently published randomized trial investigated whether high-dose statin treatment would attenuate arterial 18FDG activity more than low-dose statin treatment.39 To this end, 76 patients with established atherosclerosis were randomized to receive either daily 10 mg or 80 mg of atorvastatin. Treatment effects were assessed with 18FDG PET/ CT at baseline and at 4 and 12 weeks follow-up. At 4 weeks, arterial 18FDG activity was significantly reduced compared with baseline for both the 10 mg and 80 mg groups. At 12 weeks, an additional relative reduction was observed for the 80 mg group only, suggesting a dose–response relationship between statin therapy and reduction of arterial 18FDG activity. In addition to statins, several other drugs aimed at attenuating atherosclerosis have been evaluated with 18FDG PET. However, both vitamin B therapy and rilapladib, an inhibitor of lipoprotein-associated phospholipase A2, seem to be ineffective in attenuating the arterial 18FDG signal.40,41
PATHOPHYSIOLOGY In addition to risk stratification and treatment evaluation, assessment of plaque biology is another major domain for 18FDG PET imaging of atherosclerosis. Studies investigating inflammation (18FDG uptake), arterial mineral deposition (Na18F uptake), and vascular calcification, as seen on CT, have shown that these entities can vary among different parts of the arterial tree.42–44 It has been suggested that each marker represents distinct phases of atheroma formation. Recently, this theory found support in a retrospective longitudinal 18FDG PET/CT study.45 In 137 patients who underwent serial 18FDG PET/ CT examinations, baseline arterial 18FDG retention significantly related to subsequent vascular calcification at follow-up, even after adjustment for traditional cardiovascular risk factors. These data suggest that vascular calcification, a marker of plaque progression, seems to be preceded by vascular inflammation. Therefore, it seems that 18 FDG PET combined with Na18F PET and CT can play a synergistic role in assessment of atherosclerotic disease progression and potentially plaque and patient vulnerability.
PET Imaging of Atherosclerosis
Fig. 1. Maximum-intensity projection PET images acquired 3 hours after administration of approximately 4 MBq of 18FDG per kilogram of body weight. (A) 25-year-old man without traditional cardiovascular risk factors. Uptake of 18FDG was absent in the arterial system. (B) 66-year-old man with hypertension, hypercholesterolemia, and extensive retention of 18FDG in the femoral/popliteal arteries (black arrowheads) and subclavian/brachial arteries (white arrowheads).
LIMITATIONS 18 FDG PET imaging of atherosclerosis has several limitations. Foremost, 18FDG uptake is not specific for atherosclerosis. Therefore, detecting arterial
18
FDG uptake next to other 18FDG avid structures can be challenging. This is particularly problematic when imaging the coronary arteries, generally regarded as the culprit artery in patients suffering
Fig. 2. Axial CT (A) and fused 18FDG PET/CT (B) images of a 36-year-old man demonstrating 18FDG accumulation in the right carotid artery (white arrowhead) and left carotid artery (black arrowhead).
3
4
Blomberg & Høilund-Carlsen
Fig. 3. Axial CT (A) and fused 18FDG PET/CT (B) images of a 36-year-old man demonstrating 18FDG accumulation in the ascending aorta (white arrowheads) and descending aorta (black arrowhead).
Fig. 4. Axial CT (A) and fused 18FDG PET/CT (B) images of a 37-year-old woman showing the heart at the level of the left main coronary artery. Uptake of 18FDG in the myocardium was low. Therefore, 18FDG accumulation was detectable in the left main (black arrowhead), left circumflex (black arrow), and left anterior descending coronary artery (white arrow). Furthermore, 18FDG retention was observed in the ascending and descending aorta (white arrowheads).
Box 1 Suggestions for an imaging protocol The recommended time between The recommended
18
FDG administration and PET acquisition is 180 minutes.53,54
18
FDG dosage lies between 185 and 300 MBq.55
A blood glucose level less than 7.0 mmol/L (w126 mg/dL) is advised.55 At 180 minutes, the recommended acquisition time per bed position is 3.5 minutes. PET image reconstruction should take attenuation, scatter, random coincidences, and scanner dead time into account. Attenuation-corrected PET images are acquired by coregistration of a whole-body low-dose CT image (140 kV tube voltage, 30–110 mA tube current, 0.8 s gantry rotation time, slice thickness 3.75 mm). The estimated effective radiation dosage per whole-body
18
FDG PET/CT is approximately 7 mSv.
PET Imaging of Atherosclerosis from a myocardial infarction. High myocardial 18 FDG retention and cardiac motion artifacts prevent accurate detection of coronary 18FDG uptake. However, imaging the coronary arteries is possible in conditions in which myocardial glucose metabolism is low, such as after fasting or dietary preparation (Fig. 4). Nonetheless, coronary 18FDG PET imaging with dietary preparation has been applied with varying succes.46–49 Other obstacles hampering atherosclerosis imaging with 18FDG PET are a lack of standardized and validated imaging protocols. Box 1 proposes an 18FDG PET/CT imaging protocol optimized for atherosclerosis imaging. Also in need of standardization and validation are quantification methodologies.50
SUMMARY Initial results represent important first steps in determining the feasibility and clinical benefit of 18 FDG PET imaging for early atherosclerotic disease. Prospective long-term follow-up studies are now needed to assess the risk stratification capabilities of 18FDG PET compared with currently established methods, such the Framingham risk score, the coronary calcium score, and other imaging modalities. Similarly, treatment evaluation studies require large randomized controlled trials. Other obstacles that require attention include standardization and validation of imaging and quantification protocols.51,52
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