18F-Fluoride as a marker of unstable atheroma – a perspective

Table of Contents

PERSPECTIVE ARTICLE

H. William Strauss1,* Giuliano Mariani2, Duccio Volterrani2

1Section of Molecular Imaging and Therapy, Memorial Sloan Kettering Cancer Center, New York, NY

2Division of Nuclear Medicine, Department of Translational Medicine and Advanced Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

Abstract

The techniques currently available to detect myocardial and cerebral ischemia identify patients with advanced atherosclerosis. Localization and characterization of atheroma prior to a clinical event would allow a therapeutic intervention before any loss of function due to ischemia or infarction. To achieve a high level of specificity, the imaging technique should highlight lesions with a potential to cause a clinical event. Several radiopharmaceuticals have been described to identify inflamed, thin-cap atheroma. Of these, ionic 18F- as fluoride ion, may be the most useful. Preliminary studies suggest that 18F- does not usually localize in areas of dense vascular calcification, but does localize in areas of microcalcification. Although the local pathophysiology required for fluoride localization is not fully understood, it appears that localization occurs in regions of severe inflammation. The lack of significant uptake in normal myocardium or normal brain, suggest that low levels of fluoride uptake should provide a sufficient signal to detect small lesions. Although more work is needed to develop standard methods of quantitation and image mapping, 18F-PET-CT imaging may be useful to identify vulnerable atheroma.

Keywords: 18F; atheroma; PET-CT; vulnerable plaque; microcalcification.

Perspective

Vascular calcification is a marker of atherosclerosis [1]. To determine if atherosclerosis is a new disease, caused in part by sugary drinks and salty snacks, or is a disease that has afflicted humans for millennia, investigators performed CT scans on mummies from Egypt, Peru, Pueblo Indians from southwest United States and Unangan people from the Aleutian Islands. The CT scans demonstrated calcification of major vessels in 34% of specimens from each population [2]. The mummies were estimated to have lived from as long as several thousand years ago to as recently as several hundred years ago.

Current understanding of atherosclerosis suggests that atheroma begin with an endothelial injury, especially at sites of shear stress [3]. The damaged endothelial cell allows low-density lipoprotein cholesterol to leak into the subendothelium. The injury elicits a repair response, where surrounding endothelial cells proliferate to replace the damaged cells, thus resulting in intimal thickening [4]. The lipid is trapped as the new endothelial cells replace the damaged cells. The presence of subendothelial lipid causes an inflammatory response of the overlying endothelium, resulting in expression of chemotactic peptides, recruiting monocytes to the site [5].

Monocytes traverse the endothelium, transform into macrophages and begin the job of removing the irritating lipid by ingesting and catabolizing the noxious material. The phagocytic macrophages increase their metabolic rate, both to allow the cells to migrate to the site of lipid deposition and to phagocytize/catabolize the lipoprotein cholesterol.

In the process of catabolizing the lipid, the macrophages oxidize the lipid [6]. Oxidized cholesterol is extremely toxic to the macrophages, causing the cells to die – either by initiating apoptosis, or a process that is a combination of apoptosis and oncosis [5,7]. Due to intense metabolic activity, the macrophages produce free radicals and release a variety of proteases in the lesion, resulting in further inflammation [8]. In the presence of persistent or recurring endothelial damage, more LDL cholesterol leaks into the subendothelium, increasing inflammation, resulting in a lesion that histologically looks like an abscess.

In the presence of persistent inflammation macrophages and adjacent smooth muscle cells produce proteases, digesting the fibrous barrier. As the separation between lesion and flowing blood decreases to <65 µm, the lesion becomes vulnerable to rupture [9]. Only a small fraction of plaques that rupture (possibly 1 out of 100) result in clinical events (Fuster V, Mount Sinai Medical Center, New York, NY, personal communication). Identifying the presence and location of vulnerable plaques can direct systemic, or, if sensitive and specific enough, identify the requirement for direct mechanical intervention.

Detection of metabolically active, vulnerable atheroma has been a major goal of nuclear cardiology since the birth of the field, over 60 years ago. Table 1 is a partial list of radiopharmaceuticals advocated for detecting and localizing atherosclerosis.

AGENT/MODALITYTARGET
X-ray (Ref 10)Large vessel calcification; identify the presence of atherosclerosis
Autologous LDL (Ref 11)Localize lipid-laden plaques
Antibodies recognizing oxidized LDL (Ref 12)Localize inflamed lesions
Chemoattractant peptides (Ref 13)Localize vascular inflammation
[18F]FDG (Ref 14, 15)Lesions with inflammation, high macrophage content and hypoxia
[18F]-Fluoride (Ref 16)
Lesions with active calcification
Annexin V (Ref 17)Apoptosis

Table 1. An incomplete list of agents to localize atheroma.

Vascular calcification, as detected on current generation CT scans, designates areas of inflammation that have been walled off. These calcific lesions are more of a tombstone than a site of ongoing inflammation, as indicated by the very low concordance between sites of FDG vascular uptake (as a marker of inflammation) and calcification [18]. In a multicenter trial [19], the highest quartile of patients with >130 Hounsfield units of coronary vascular calcium predicted cardiac events over the next 3 years in ~ 1% of the population. As a result, while the presence of calcium means the presence of atherosclerosis, it does not provide sufficient information on the likelihood of a clinical event within the next few years.

Similarly, the use of radiolabeled LDL in patients with documented carotid disease provides important information about the striking permeability of these highly inflamed lesions to large molecules, such as autologous LDL cholesterol [11]. However, preparation of autologous cholesterol is complex, requiring experienced staff to perform the separation and purification of the LDL and label the protein.

Antibodies recognizing oxidized LDL [12] radiolabeled with iodine-125 (125I-MDA2) and with 99mTc demonstrated co-localization of oxidized LDL antibody with regions demonstrating lipid deposition in the aorta of LDLR-/- mice. In mice treated with a reduced cholesterol diet or antioxidant intervention, there was a marked decrease of antibody uptake in regions that contained lipid. Although this technique is useful to identify areas of intense inflammation, it is complex for a screening study.

Radiolabeled chemoattractant peptides [13] localize in regions of re-endothelializing vascular injury in cholesterol fed rabbits. This observation is consistent with the known pathophysiology of atheroma, but occurs very early in the process, and may be too sensitive for clinical use.

Localizing areas of vascular inflammation with 18F-fluorodeoxyglucose (18F-FDG) [14] has been useful to demonstrate the relative effectiveness of dietary and pharmacologic therapy on inflammation in the carotid arteries [20]. While this technique is straightforward to use in large vessels, it is problematic to apply in the coronary arteries, due to physiologic uptake in the myocardium of ~ 50% of patients. Joshi et al. [21] compared the coronary uptake of 18F as ionic fluoride to localization of 18F-FDG in patients myocardial infarction (n=40) and stable angina (n=40). The authors demonstrated the most intense localization of fluoride in the culprit lesion, while 18F-FDG localization was ‘often obscured by myocardial uptake, and where discernible, there was no differences between culprit and non-culprit plaques.’

Apoptosis is an integral step in the pathophysiology of vulnerable plaque [22]. Unfortunately, studies comparing 99mTc- annexin to carbon-14 labeled 2-deoxyglucose in apo e-/- mice, demonstrated 6.3 fold greater uptake of deoxyglucose to annexin V in regions of atheroma. The low uptake of annexin in experimental atheroma makes it difficult to detect small lesions by external imaging in vivo.

The pathophysiology demonstrated by fluoride imaging of atheroma is not fully elucidated.  A review the history of this imaging agent may shed some light on this complex subject. In 1954 a study of the biodistribution of 18F-fluoride in 25 week old rats by Wallace-Durbin [23] reported that at 1 (n=10), 4 (n=10) and 9 (n=12) hours after intravenous injection ~50% of the dose was in the skeleton and ~30% in the urine. At 1 hour there was 5.6% of the injected dose in skeletal muscle and 1.4% of the injected dose in the blood volume (most in plasma); by 4 hours skeletal muscle decreased to 0.88%/organ and blood to 0.15%. An autoradiograph of the distal femur demonstrated striking uptake in the epiphysis. Wallace-Durbin concluded that there was ‘no significant deposition of 18F in the soft tissues…’

The use of 18F-fluoride for imaging the skeleton in human subjects was initially described by Blau and colleagues in 1962 [24]. In 1972 the authors describe their experience with this tracer [25] over a decade of clinical use. The authors suggest that the major mechanism of uptake is ion exchange in hydroxyapatite crystals – most likely with hydroxyl (OH–) ions. Individual hydroxyapatite crystals are 20×5×5 µm, providing ‘an enormous surface area’ (~300 m2/g) for localization. Blau described the passage of a fluoride ion from the blood to the bone crystal as follows:

The fluoride ion ‘must pass (1) from the plasma, (2) through the extracellular fluid, (3) into the shell of bound water surrounding the crystal, (4) onto the surface and (5) into the interior of the crystal. The first 3 steps have half times in minutes. Step 4 is probably measured in hours and step 5 takes days or weeks. However, once ions have entered the bound water shell they are essentially part of the bone…’

‘Areas of high uptake…result from any processes that increase exposed bone crystal and/or the blood flow.’

In the seminal publication the authors include a table, listing soft tissue abnormalities that had been detected with fluoride imaging, including dystrophic calcification in: calcific tendinitis, healing postoperative sites, soft tissue metaplasia and dental abscess.

Vascular calcification often occurs as a result of focal inflammation. In a longitudinal study of 137 patients, Abeldaky et al. [26] used the metabolic marker, [18F]FDG, to perform [18F]FDG PET/CT scans on two occasions, 1-5 years apart. Focal uptake of [18F]FDG in specific regions of the thoracic aorta were identified on the initial scan. The CT scans of the initial and follow-up studies were sent to a separate group of investigators, who evaluated these same aortic segments for the presence of calcium at baseline (>130 HU) and identified any change at follow-up: 9% of aortic segments (n=67) demonstrated increased calcification.

The sites of new calcification occurred in areas that had increased [18F]FDG uptake on the baseline scan. Similarly, Derlin and colleagues [27] demonstrated ionic 18F– fluoride deposition in the vasculature (carotid, iliac and femoral arteries as well as the aorta) in 57 of 75 patients referred for 18F-fluoride bone scans as part of an oncologic evaluation. However, there was co-localization with arterial calcification in only 12% of patients, suggesting that 18F-fluoride uptake and dense calcium likely represent different phases of an atheroma.

This was confirmed in a study of 45 patients who had both [18F]FDG and 18F-fluoride bone scans, where only 6.5% of lesions had colocalization of both tracers in regions without gross calcification, and 14.5% demonstrated colocalization in regions of calcification [28].

The lack of 18F-fluoride localization in regions of dense calcium suggests that these regions have a much smaller surface area for rapid exchange than regions of microcalcification. Regions of early dystrophic vascular calcification, on the other hand, occur in regions recovering from acute inflammation. These areas have a rich vascular network of ‘immature endothelial tubes with leaky imperfect linings [29].

These regions would have rapid delivery of fluoride ion to the developing calcium-organic material complex that forms the basis of vascular microcalcification [30], and would localize at a time in the evolution of the plaque when the lesion is vulnerable. Microcalcifications range from 5 to 60 µm, too small to be defined on conventional CT. However, when atheromas are subjected to high-resolution micro-CT these lesions are readily visible [31]. Based on the kinetics of fluoride localization in dystrophic calcification, it is likely that focal 18F-fluoride uptake in atheroma occurs in lesions in this critical phase.

Clinical studies are required to validate this hypothesis. However, based on PET/CT studies to date [21] the future of 18F-fluoride imaging for the localization of vulnerable atheroma looks promising. Due to significant lesion uptake and high target to background ratios, it may be possible to develop a score based on a combination of lesion SUV (in spite of the partial volume effects) and the number of lesions in a vascular territory. This score may determine if pharmacologic therapy will be sufficient or revascularization is necessary.

Conflict of interest

The authors confirm that this article content has no conflict of interest.

References

Key References: 2, 9, 13, 14, 18, 21, 26, 28, 30, 31

  1. Evrard S, Delanaye P, Kamel S, Cristol JP, Cavalier E. On behalf of the SFBC/SN joined working group on vascular calcifications; On behalf of the SFBC/SN joined working group on vascular calcifications. Vascular calcification: from pathophysiology to biomarkers. Clin Chim Acta. 2014 Sep 16. doi:10.1016/j.cca.2014.08.034. PMID: 25236333. [PubMed Abstract]
  2. Thompson RC, Allam AH, Lombardi GP, et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet. 2013; 381: 1211-1222. [CrossRef] [PubMed Abstract]
  3. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanism of plaque formation and rupture. Circ Res. 2014; 114; 1852-1866. [CrossRef] [PubMed Abstract]
  4. Stary HC, Blankenhorn DH, Chandler AB, et al. A definition of the intima of human arteries and of its atherosclerosis-prone regions. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb. 1992; 12: 120-134. [CrossRef] [PubMed Abstract]
  5. Libby P, Tabas I, Fredman G, Fusher EA. Inflammation and its resolution in coronary syndromes. Circ Res. 2014; 114: 1867-1879. [PubMed Abstract]
  6. Maiolino G, Rossitto G, Caielli P, Bisogni V, Rossi GP, Calò LA. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators Inflamm. 2013:714653. [CrossRef] [PubMed Abstract]
  7. Blankenberg FG, Strauss HW. Recent advances in the molecular imaging of programmed cell death: part I -pathophysiology and radiotracers. J Nucl Med. 2012; 53:1659-1662. [CrossRef] [PubMed Abstract]
  8. Silvestre-Roig C, de Winther MP, Weber C, Daemen MJ, Lutgens E, Soehnlein O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circ Res. 2014; 114: 214-226. [CrossRef] [PubMed Abstract]
  9. Narula J, Nakano M, Virmani R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol. 2013; 61:1041-1051. [CrossRef] [PubMed Abstract]
  10. Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler Thromb Vasc Biol. 2014; 34: 724-736. [CrossRef] [PubMed Abstract]
  11. Lees RS, Lees AM, Strauss HW. External imaging of human atherosclerosis. J Nucl Med. 1983; 24: 154-156. [PubMed Abstract] [Reference Source]
  12. Tsimkas S. Noninvasive imaging of oxidized low-density lipoprotein in atherosclerotic plaques with tagged oxidation-specific antibodies. Am J cardiol. 2002; 21: 22L-27L. [CrossRef] [PubMed Abstract]
  13. Ohtsuki K, Hayase M, Akashi K, Kopiwoda S, Strauss HW. Detection of monocyte chemoattractant protein-1 receptor expression in experimental atherosclerotic lesions: an autoradiographic study. Circulation. 2001; 104: 203-208. [CrossRef] [PubMed Abstract]
  14. Rudd JH, Narula J, Strauss HW, et al. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time? J Am Coll Cardiol. 2010; 55: 2527-2535. [PubMed Abstract]
  15. 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: 603-614. [PubMed Abstract]
  16. Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation. 2003; 108: 3134-3139. [CrossRef] [PubMed Abstract]
  17. Derlin T, Wisotzki C, Richter U, et al. In vivo imaging of mineral deposition in carotid plaque using 18F-sodium fluoride PET/CT: correlation with atherogenic risk factors. J Nucl Med. 2011; 52: 362-368. [CrossRef] [PubMed Abstract]
  18. Dunphy MP, Freiman A, Larson SM, Strauss HW. Association of vascular 18F-FDG uptake with vascular calcification. J Nucl Med. 2005; 46: 1278-1284. [PubMed Abstract]
  19. Criqui MH, Denenberg JO, McCleland RL, et al. Abdominal Aortic Calcium, Coronary Artery Calcium, and Cardiovascular Morbidity and Mortality in the Multi-Ethnic Study of Atherosclerosis. Arterscler Thromb Vasc Biol. 34: 1574-1579. [CrossRef] [PubMed Abstract]
  20. Tahara N, Kai H, Ishibashi M, Nakaura H, Kaida H, Baba K, Hayabuchi N, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol. 2006; 48: 1825-1831. [PubMed Abstract] [Reference Source]
  21. 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: 705-713. [CrossRef] [PubMed Abstract]
  22. Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie FD, Virmani R. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ. 2013; 22: 399-411. [CrossRef] [PubMed Abstract]
  23. Wallace-Durbin P. The metabolism of Fluorine in the rat using F18 as a tracer. J Dent Res. 1954; 33: 789-800. [CrossRef] [PubMed Abstract]
  24. Blau M, Nagler W, Bender MA. Fluorine-18: A new isotope for bone scanning. J Nucl Med. 1962; 3: 332-334. [PubMed Abstract]
  25. Blau M, Ganatra R, Bender MA. 18F-fluoride for bone imaging. Semin Nucl Med. 1972; 2: 31-37. [CrossRef] [PubMed Abstract]
  26. Abdelbaky A, Corsini E, Figueroa AL, et al. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study. Circ Cardiovasc Imag. 2013; 6: 747-754. [CrossRef] [PubMed Abstract]
  27. Derlin T, Richter U, Bannas P, et al. Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med. 2010; 51: 962-965. [CrossRef]
  28. Derlin T, Tóth 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: 1020-1027. [CrossRef] [PubMed Abstract]
  29. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005; 25: 2054-2061. [CrossRef] [PubMed Abstract]
  30. Hutcheson JD, Maldonado N, Aikawa E. Small entities with large impact: microcalcifications and atherosclerotic plaque vulnerability. Curr Opin Lipidol. 2014; 25: 327-332. [CrossRef] [PubMed Abstract]
  31. Kelly-Arnold A, Maldonado N, Laudier D, et al. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc Natl Acad Sci USA. 2013; 110: 10741-10746. [CrossRef] [PubMed Abstract]

Suggested reading

  1. Vesey A, Newby DE, Dweck MR. Will 18F-sodium fluoride PET-CT imaging be the magic bullet for identifying vulnerable coronary atherosclerotic plaques? Curr Cardiol Rep. 2014; 16(9): 521. [PubMed Abstract]
  2. Chen W, Dilsizian V. Targeted PET/CT imaging of vulnerable atherosclerotic plaques: microcalcification with sodium fluoride and inflammation with fluorodeoxyglucose. Curr Cardiol Rep. 2013; 15(6): 364. [CrossRef] [PubMed Abstract]
  3. Quirce R1, Banzo I, Martínez-Rodríguez I, et al. New insight of molecular imaging into the atheroma biology: (18)F-fluoride PET/CT and 18F-FDG PET/CT of 3 carotid plaques in asymptomatic neurologic patient. Clin Nucl Med. 2013; 38(6): 451-452. [PubMed Abstract]
  4. Quirce R, Martínez-Rodríguez I, De Arcocha Torres M, et al. Contribution of 18F-sodium fluoride PET/CT to the study of the carotid atheroma calcification. Rev Esp Med Nucl Imagen Mol. 2013; 32(1): 22-25. [CrossRef] [PubMed Abstract]
  5. Beheshti M, Saboury B, Mehta NN, et al. Detection and global quantification of cardiovascular molecular calcification by fluoro18-fluoride positron emission tomography/computed tomography-a novel concept. Hell J Nucl Med. 2011; 14(2): 114-120. [PubMed Abstract]

Article information

Corresponding author: H. William Strauss.

Copyright: © 2014 Strauss HW et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are cited.

How to cite: Strauss HW, Mariani G, Volterrani D. 18F-Fluoride as a marker of unstable atheroma – A Perspective. J. Diagn. Imaging Ther. 2014; 1(1): 129-136 (https://dx.doi.org/10.17229/jdit.2014-1118-009).

Article history: Received 06 November 2014; Revised 14 November 2014; Accepted 17 November 2014; Published online 18 November 2014.

Archive Link: JDIT-2014-1118-009

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