jnm158329 974..975


I N V I T E D P E R S P E C T I V E S

Finding Calcium in Noncalcified Lesions: 18F-Fluoride Offers
Insights into Atheroma Evolution

H. William Strauss1,2, Jagat Narula2, and Takehiro Nakahara2

1Molecular Imaging and Therapy Section, Memorial Sloan Kettering Cancer Center, New York, New York; and 2Cardiology Section,
Mount Sinai Icahn School of Medicine, New York, New York

It is not what you look at that matters, it is what you see.
—Henry David Thoreau

Intimal arterial calcification is “a pervasive and likely inevitable
program that is intimately entwined with aging, atherosclerosis,
and cardiovascular disease” (1). Since 1990, vascular calcification
has been quantitated (2) and correlated with the likelihood of
cardiovascular events (3). The clinical significance of intimal ar-
terial calcification, however, remains controversial. Shaw et al. (4)
reviewed the issues in a recent editorial entitled, “The Never-Ending
Story on Coronary Calcium: Is It Predictive, Punitive, or Protective?”
To understand why this controversy exists, it may be helpful to
evaluate the pathophysiology of atheroma.
Calcification of atheroma occurs in inflamed lesions. Lesions

are inflamed because low-density lipoprotein (LDL) cholesterol is
trapped in the subintimal space, irritating the overlying endothe-
lium and leading to the production of chemotactic factors. The

See page 1019

chemotactic factors attract mononuclear cells to the site (5,6).
Mononuclear cells transform to tissue macrophages, enter the lesion,
and phagocytize the LDL cholesterol complex. This complex is
difficult to catabolize, and in the process of breaking down the pro-
tein–lipid complex, oxidized LDL is formed. Oxidized LDL is toxic
to the macrophage, resulting in apoptosis or necrosis of the cell. Loss
of cell membrane integrity in necrotic cells allows oxidized LDL
and numerous proteases to be released into the lesion, increasing the
inflammation. The resulting toxic environment induces apoptosis of
some adjacent cells, such as smooth muscle cells, causing release of
matrix vesicles (7) and further increasing inflammation. The usual
clean-up and recycling of elements from these dead cells by effer-
ocytosis is impaired (8) by a combination of the age of the patient
and the severity of the inflammation (9).The persistence of the toxic
lesion attracts additional monocytes, mast cells, and lymphocytes,

which produce factors such as bone morphogenetic protein–2 that
lead to the formation of microcalcifications (10).
Microcalcifications are seen in lesions with pathologic intimal

thickening and appear as microscopic foci, typically between 0.5
and 15 mm, on histopathology (7). These lesions are too small to
be resolved by conventional CT, which has a spatial resolution of
about 6 line pairs per centimeter in a high-contrast phantom (11)

and about 5 mm in low-contrast objects (12). As lesions progress

through multiple cycles of inflammation and healing, the layers

of calcification progress from microcalcifications to sheets of

calcium large enough and dense enough to be seen on CT.
In addition to calcification, another characteristic of atheroma is

increased angiogenesis. Increased vascularity of the lesion enhan-

ces delivery of circulating substances to it. Even large molecules

such as radioiodinated autologous LDL (13), which has a molecu-

lar weight of about 3 · 106, localize in carotid atheroma within
hours of intravenous injection (14), likely because of mixing and

retention in the large intralesional pool of LDL. Given the local-

ization of large molecules, it is not surprising that small particles

such as radiofluoride ions (18F as fluoride ion) also localize in

these lesions (15). It is likely that the mechanism of fluoride

localization is due to adsorption of the ion on the small dystrophic

particles of calcification (with a large surface area).
Identifying these microcalcifications is important, because

a finite element analysis of 35,000 microcalcifications in lesions

from 22 patients demonstrated that—depending on the size and

distance between particle pairs and the orientation of the particles

with reference to the tensile axis of the cap—the local tissue stress

could increase by a factor of 5 (16), raising the likelihood of cap

rupture.
In this issue of The Journal of Nuclear Medicine, Fiz et al. (17)

describe the relationship between ionic 18F (18F-NaF) localization
in the infrarenal abdominal aorta and the distribution of CT-visible
calcification on PET/CT images. The authors observed an average
of 6.2 sites of arterial calcification per patient (providing 397 foci
of arterial calcification for analysis). There was an inverse correla-
tion between 18F-NaF localization and Hounsfield unit plaque den-
sity. In fact, the authors found 18F-NaF hot spots at sites without
visible calcification in 86% of patients. 18F-NaF intensity at these
sites was higher than that observed at sites with calcification on CT.
The data reported by Fiz (17) suggest that 18F-NaF localizes at

sites of calcification that are invisible at the current clinical CT

resolution. Although many of these lesions may not be at immi-

nent risk of rupture (because of the distance between foci or their

orientation with reference to the tensile strength of the plaque), it

Received May 4, 2015; revision accepted May 5, 2015.
For correspondence or reprints contact: H. William Strauss, Memorial

Sloan Kettering Cancer Center, 1275 York Ave., Room S-113A, New York,
NY 10021.
E-mail: straussh@mskcc.org
Published online May 21, 2015.
COPYRIGHT © 2015 by the Society of Nuclear Medicine and Molecular

Imaging, Inc.
DOI: 10.2967/jnumed.115.158329

974 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 56 • No. 7 • July 2015

mailto:straussh@mskcc.org


seems that these lesions are a seat of intense activity, with an
abundance of inflammation, cytokine excess, and ongoing cellular
damage. Such active lesions may result in rapid expansion of the
necrotic core and progression of plaque, which happen to be
strong predictors of eventful plaques (18).
The current investigation is an exciting hypothesis generating

study, and we need prospective outcomes data to establish the
value of serial 18F-NaF vascular imaging. 18F-NaF imaging might
evolve to supplement the overall prognostic importance of the
Agatston score by offering lesion-specific prognostic information.

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FINDING CALCIUM IN NONCALCIFIED LESIONS • Strauss and Narula 975

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http://https://health.siemens.com/ct_applications/somatomsessions/index.php/image-quality-in-computed-tomography-2/