Introduction
Arterial calcification on CT is used as a marker for the presence of intimal calcification (atherosclerosis) and medial arterial calcification. Microcalcifications (< 50 µm) are observed in the early stages of the calcification process and are possibly associated with plaque rupture, whereas macrocalcifications contribute to stability of atherosclerotic plaques.
1 In addition, microcalcifications in the internal elastic lamina and in the tunica media,
2,
3 may be related to arterial stiffening.
4 CT allows to identify macrocalcifications of over 200 µm in diameter.
5 Sodium 18F-fluoride (
18F-NaF) PET/CT is a novel imaging technique that can visualize smaller calcifications.
6‐
10 In the femoral arteries,
18F-NaF PET can visualize ongoing (medial and intimal) calcification.
11 In the coronaries
18F-NaF PET is associated with high risk plaque features and plaque rupture.
6 In patients with diabetes, additional to atherosclerosis, medial arterial calcification (MAC or Mönckeberg’s sclerosis) is highly prevalent and is associated with increased arterial stiffness, hypertension, distal symmetrical neuropathy, chronic kidney disease, cardiovascular and all-cause mortality.
12‐
14 MAC is observed in arteries of the lower extremity across the entire length.
3 A recent study showed that increased
18F-NaF PET accumulation in the femoral arteries is associated with diffuse calcium deposition and significantly correlates with cardiovascular risk factors.
11 Several studies investigated determinants of
18F-NaF uptake in oncologic patients.
11,
15 While the use of
18F-NaF is increasing, the available data are limited regarding its uptake values and potential uptake modifiers in high CVD risk groups such as diabetes patients. The goal of this study is to investigate the potential determinants of
18F-NaF uptake as a marker of arterial calcification in patients with type 2 diabetes and a history of arterial disease.
Discussion
This study provides several observations that contribute to our understanding of the determinants of 18F-NaF PET in the femoral arteries of patients with type 2 diabetes and a history of arterial disease. Firstly, we showed that femoral calcium mass on CT is positively associated with 18F-NaF uptake. Second, several cardiovascular risk factors including total cholesterol, triglycerides and HbA1c were associated with 18F-NaF uptake in patients with type 2 diabetes. Together, these data suggest that 18F-NaF uptake is an important imaging biomarker of arterial disease burden both related to dyslipidemia and diabetes control even in extensively treated patients.
Previous research showed that multiple cardiovascular risk factors are associated with
18F-NaF uptake. Derlin et al
15 examined
18F-NaF in the carotid arteries in 269 oncologic patients.
18F-NaF uptake was significantly associated with age, male sex, hypertension and hypercholesterolemia. In a different study among 409 oncologic patients, the association between
18F-NaF accumulation in femoral arteries with cardiovascular risk factors and calcified plaque burden was demonstrated.
11 In both studies, hypercholesterolemia was associated with increased
18F-NaF uptake, which is in line with our study. An association between HbA1c and
18F-NaF uptake, had been observed in healthy controls.
18 In patients with diabetes, high HbA1c is known to be associated with osteocalcin, which supports the concept of vascular calcification in patients with diabetes.
19 Blomberg et al
18 investigated
18F-NaF uptake in the coronary arteries of 89 healthy adults. According to their results age, female sex and BMI were independent determinants of increased coronary
18F-NaF uptake. In our study we did not find an association between age, sex or BMI and
18F-NaF uptake. The differences in associations between cardiovascular determinants and
18F-NaF uptake compared to our study could be explained by the differences in study population (our cohort consisted predominantly out of males with a high BMI), investigated vessels beds
20 and inclusion criteria.
18F-NaF uptake is significantly higher in microcalcifications compared to macrocalcifications.
21 Irkle et al
21 demonstrated using preclinical μPET/μCT that microcalcifications have no barriers for penetration, while
18F-NaF cannot penetrate into the deeper layers of macrocalcifications. Also, microcalcifications have a relatively big surface area compared to their volume. In a prior longitudinal study, we observed that areas without calcification on CT, but with increased
18F-NaF uptake, had more arterial calcification at follow-up.
17 These could represent microcalcifications not yet detectable on CT.
17 In the current study CT detected arterial calcification was related to
18F-NaF uptake, suggesting a significant effect of large calcium depositions on tracer uptake with clinical PET/CT systems.
An important strength of the current study is that images were acquired 90 min after tracer injection. The 90 min time-point is considered to be advantageous, because of the balance between signal-to-background ratio and patient comfort. For comparability with other studies we used TBR as our measure of
18F-NaF uptake for research.
15 There is debate on how to quantify arterial calcification with NaF PET.
22‐
24 We calculated the TBR using the average of the SUVmax of each femoral artery slice. Though SUVmax is sensitive to noise, it can also be a good measure of the maximum disease burden in a slice.
22,
23 By averaging (76 slices per patient) the noise effect is reduced to some extent. Others advocate the SUVmean for an individual slice,
24 which is less limited by noise, but also averages non-diseased parts of the artery and the blood pool. Differences in PET SUV quantification will influence the observed result therefore it would be important to achieve uniform quantification methods. Other limitations are the relative small sample size and the lack of prospective outcome data.
In conclusion, we showed that cardiovascular risk factors including total cholesterol, triglycerides and HbA1c are associated with 18F-NaF uptake and calcification in the femoral arteries in patients with type 2 diabetes mellitus and a history of arterial disease. Our findings show that 18F-NaF uptake can be an imaging biomarker of arterial disease burden both related to dyslipidemia and diabetes control. Larger studies are needed to investigate whether these findings are generalizable to non-diabetic patients with cardiovascular diseases and if (further) modification of these risk factors is beneficial for 18F-NaF uptake and outcome.
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