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Background: Perfusion deficits contribute to symptom severity, morbidity, and death in peripheral artery disease (PAD); however, no standard method for quantifying absolute measures of skeletal muscle perfusion exists. This study sought to preclinically test and clinically translate a positron emission tomography (PET) imaging approach using an atherosclerosis-targeted radionuclide, fluorine-18-sodium fluoride ( 18 F-NaF), to quantify absolute perfusion in PAD., Methods and Results: Eight Yorkshire pigs underwent unilateral femoral artery ligation and dynamic 18 F-NaF PET/computed tomography imaging on the day of and 2 weeks after occlusion. Following 2-week imaging, calf muscles were harvested to quantify microvascular density. PET methodology was validated with microspheres in 4 additional pig studies and translated to patients with PAD (n=39) to quantify differences in calf perfusion across clinical symptoms/stages and perfusion responses in a case of revascularization. Associations between PET perfusion, ankle-brachial index, toe-brachial index, and toe pressure were assessed in relation to symptoms. 18 F-NaF PET/computed tomography quantified significant deficits in calf perfusion in pigs following arterial occlusion and perfusion recovery 2 weeks after occlusion that coincided with increased muscle microvascular density. Additional studies confirmed that PET-derived perfusion measures agreed with microsphere-derived perfusion measures. Translation of imaging methods demonstrated significant decreases in calf perfusion with increasing severity of PAD and quantified perfusion responses to revascularization. Perfusion measures were also significantly associated with symptom severity, whereas traditional hemodynamic measures were not., Conclusions: 18 F-NaF PET imaging quantifies perfusion deficits that correspond to clinical stages of PAD and represents a novel perfusion imaging strategy that could be partnered with atherosclerosis-targeted 18 F-NaF PET imaging using a single radioisotope injection., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03622359.

Background: Positron emission tomography (PET)/computed tomography (CT) imaging with fluorine-18 ( 18 F)-sodium fluoride (NaF) provides assessment of active vascular microcalcification, but its utility for evaluating diabetes mellitus (DM)- and chronic kidney disease (CKD)-induced atherosclerosis in peripheral arterial disease (PAD) has not been comprehensively evaluated. This study sought to use 18 F-NaF PET/CT to quantify and compare active microcalcification on an artery-by-artery basis in healthy subjects, PAD patients with or without DM, and PAD patients with or without CKD. Additionally, we evaluated the contributions of DM, CKD, statin use and established CT-detectable calcium to 18 F-NaF uptake for each lower extremity artery., Methods: PAD patients (n = 48) and healthy controls (n = 8) underwent lower extremity 18 F-NaF PET/CT imaging. Fused PET/CT images guided segmentation of arteries of interest (i.e., femoral-popliteal, anterior tibial, tibioperoneal trunk, posterior tibial, and peroneal) and quantification of 18 F-NaF uptake. 18 F-NaF uptake was assessed for each artery and compared between subject groups. Additionally, established calcium burden was quantified for each artery using CT calcium mass score. Univariate and multivariate analyses were performed to evaluate DM, CKD, statin use, and CT calcium mass as predictors of 18 F-NaF uptake in PAD., Results: PAD patients with DM or CKD demonstrated significantly higher active microcalcification (i.e., 18 F-NaF uptake) for all arteries when compared to PAD patients without DM or CKD. Univariate and multivariate analyses revealed that concomitant DM or CKD was associated with increased microcalcification for all arteries of interest and this increased disease risk remained significant after adjusting for patient age, sex, and body mass index. Statin use was only associated with decreased microcalcification for the femoral-popliteal artery in multivariate analyses. Established CT-detectable calcium was not significantly associated with 18 F-NaF uptake for 4 out of 5 arteries of interest., Conclusions: 18 F-NaF PET/CT imaging quantifies vessel-specific active microcalcification in PAD that is increased in multiple lower extremity arteries by DM and CKD and decreased in the femoral-popliteal artery by statin use. 18 F-NaF PET imaging is complementary to and largely independent of established CT-detectable arterial calcification. 18 F-NaF PET/CT imaging may provide an approach for non-invasively quantifying vessel-specific responses to emerging anti-atherogenic therapies or CKD treatment in patients with PAD., (© 2023. The Author(s).)

A 65-year-old man with an occluded popliteal artery aneurysm and calf claudication underwent PET/CT imaging with F-NaF to assess the status of active microcalcification in the aneurysm site and additional lower extremity arteries. CT imaging revealed macrocalcification of the aneurysm that colocalized with elevated retention of F-NaF on PET images. PET/CT detected additional distal arterial sites with focal uptake of F-NaF that did not coincide with CT-detectable macrocalcification. This report highlights a case of active microcalcification in an occlusive peripheral aneurysm using PET/CT. PET/CT may provide molecular insight into the remodeling of lower extremity aneurysms and atherosclerotic lesions.