Detection of multivessel calcific disease progression in a patient with chronic limb-threatening ischemia using fluorine-18 sodium fluoride positron emission tomography imaging

Vascular calcification contributes to morbidity and poor clinical outcomes for patients with peripheral artery disease; however, the traditional assessment of the calcium burden using computed tomography (CT) imaging or angiography represents already established disease. In the present report, we describe a 69-year-old man with chronic limb-threatening ischemia who had undergone positron emission tomography/CT imaging with fluorine-18 sodium fluoride to evaluate the relationship between baseline levels of positron emission tomography-detectable active vascular microcalcification and CT-detectable calcium progression 1.5 years later. CT imaging at follow-up identified progression of existing lesions and the formation of new calcium in multiple arteries that had demonstrated elevated fluorine-18 sodium fluoride uptake 1.5 years earlier.

High levels of arterial calcification above and below the knee can reduce limb blood flow and promote deficits in muscle perfusion, limit options for revascularization, increase the incidence of ulceration and nonhealing wounds, and contribute to worse revascularization outcomes for patients with peripheral artery disease (PAD). [1][2][3][4] Thus, a need exists for an imaging strategy that can detect the early active stages of calcific disease in the lower extremities to improve noninvasive monitoring and the detection of patients at risk of calcific disease progression.
Positron emission tomography (PET)/computed tomography (CT) imaging studies using the radionuclide fluorine-18 ( 18 F)-sodium fluoride (NaF) have demonstrated the potential of this imaging strategy for quantifying active stages of microcalcification in the cardiovascular system. 5,6 However, to date, application of 18 F-NaF PET/CT imaging has not been used in the vascular medicine community as a tool for monitoring and predicting disease progression in patients with PAD. In the present report, we describe the case of a man with chronic limb-threatening ischemia (CLTI) who had undergone baseline 18 F-NaF PET/CT imaging and follow-up CT imaging studies 1.5 years later to evaluate the relationship between the arterial uptake of 18 F-NaF and subsequent calcific disease progression in each primary artery of his symptomatic limb. The institutional review board and radiation safety committee of Nationwide Children's Hospital approved the study protocol. The patient provided written informed consent for the report of his case details and imaging studies.

CASE REPORT
A 69-year-old man with type 2 diabetes mellitus had initially presented to our multidisciplinary wound clinic with a wound on the plantar surface of his left heel/midfoot. The patient had previously been diagnosed with diabetic arthropathy and deformity of the left foot that was associated with stable collapse at Baseline 18 F-NaF PET/CT imaging revealed focal uptake of 18 F-NaF (ie, active microcalcification) in multiple arterial sites of the left limb (Fig 2, A). The corresponding follow-up CT images acquired 1.5 years later demonstrated increases in vascular calcification within the same arterial sites previously identified as having increased 18 F-NaF uptake (Fig 2, B). The popliteal artery was specifically identified as having minimal calcium with elevated 18 F-NaF uptake at baseline (Fig 3, A), which later aligned with the same region of the popliteal artery, which had significant calcium 1.5 years later (Fig 3, B). Further analysis of 18 F-NaF uptake and calcium progression in a separate region of the popliteal artery showed minimal 18 F-NaF uptake at baseline that corresponded with no subsequent progression of calcium 1.5 years later (Fig 4). In addition to the various levels of calcium progression in multiple lower extremity arteries, the patient had progressed to stage 4 CKD at the 1.5-year follow-up. The foot ulcer on the plantar surface of the left foot was stable and showed slow improvement during the duration of the 1.5-year study timeline (Fig 5).

DISCUSSION
The presence and severity of a lower extremity calcium burden has traditionally been evaluated with standard of care imaging modalities such as CT; however, calcium detected on CT images represents established calcific disease. Alternatively, 18 F-NaF PET/CT imaging allows for noninvasive monitoring of active arterial microcalcification and provides complementary molecular insight into the earlier stages of calcific disease progression. 6 However, this technique has only recently been applied to the lower extremities, 7-9 with only one study specifically focusing on evaluating patients with PAD. 9 In a recent case, Eisert et al 10 applied 18 F-NaF PET/CT imaging for a patient with PAD and suggested that uptake of 18 F-NaF might be elevated during the remodeling of lower extremity calcific aneurysms and in below-the-knee arteries. However, to the best of our knowledge, no study has assessed the prognostic value of 18 F-NaF PET- detected active microcalcification for predicting subsequent CT-detectable calcific disease progression in multiple lower extremity arteries or evaluated calcium progression in patients with PAD. Thus, in the present report, we have built on the existing literature by describing the case of a 69-year-old man with CLTI who had undergone 18 F-NaF PET/CT imaging for baseline evaluation of active vascular microcalcification and follow-up evaluation of calcium progression 1.5 years later. Our observation that calcific disease progression had occurred in multiple lower extremity arteries previously identified as having elevated uptake of 18 F-NaF also builds on recently reported studies that have demonstrated 18 F-NaF PET/CT imaging can predict for calcium progression in the coronary arteries, 11 femoral arteries, 8 and aorta. 12 Additionally, the present patient's calcific disease progression, which occurred in sequence with his CKD progression, supports a recent study that demonstrated the contributions of CKD to active vascular microcalcification (ie, 18 F-NaF uptake) in the lower extremities of patients with PAD. 9 Angiographic evaluation of the patient's left limb years earlier had revealed single-vessel runoff via the posterior tibial artery. This prior information, combined with delayed, yet progressive, healing of his left foot wound, might suggest that the patient's posterior tibial artery had remained patent enough to support limb and tissue viability. However, as the findings from the present report have shown, the posterior tibial artery demonstrated elevated uptake of 18 F-NaF at baseline and showed calcific disease progression on CT imaging 1.5 years later. Thus, this molecular imaging strategy might possess value for identifying at-risk vessels that could be the last remaining patent vessel for preserving limb integrity, which would be especially critical for patients with CLTI such as in the present report. Additionally, increasing the clinical application of 18 F-NaF PET/CT imaging to PAD might increase future opportunities for personalized medicine for patients deemed at high risk of progressing to symptomatic PAD (claudication) or CLTI because of preexisting cardiovascular risk factors, offer a noninvasive biomarker for testing responses to novel PAD therapies, and facilitate our understanding of the specific contributions of traditional PAD risk factors, such as diabetes and CKD, to calcific progression in those with PAD.

CONCLUSIONS
Hybrid PET/CT imaging with 18 F-NaF detected early evidence of active microcalcification in multiple vessels imaging of multivessel calcific disease progression. A, Baseline PET/CT imaging at study enrollment revealing various levels of CT-detectable calcium deposition in the popliteal, posterior tibial, anterior tibial, and peroneal arteries (white arrows) with active microcalcification occurring in multiple vessels, as shown by 18 F-NaF PET imaging (white arrows). B, Follow-up CT imaging 1.5 years later demonstrating new calcium or progression of existing calcium within vascular regions (yellow arrows) that were previously identified as having elevated levels of 18 F-NaF uptake (ie, active disease). SUV, Standardized uptake value.
within the symptomatic, ulcerated limb of a patient with CLTI that resulted in the appearance of new, or progression of, CT-detectable arterial calcium 1.5 years later. Our findings suggest that 18 F-NaF PET/CT imaging can be used to predict calcific disease progression on a vessel-by-vessel or lesion-by-lesion basis in patients with CLTI, thus providing a noninvasive imaging strategy for assessing the risk of lower extremity disease progression and potentially enabling future improvements to personalized medicine for patients with PAD.   Serial photographs of the patient's chronic diabetic foot wound during the 1.5-year study timeline. Evidence of prior reconstructive surgery is apparent, with slow, but progressive, healing of the wound.