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Peripheral artery disease (PAD) is classified as the narrowing or complete occlusion of the lower extremity arteries due to atherosclerosis. The risk of developing PAD increases with increased age and risk factors such as smoking, diabetes, hypertension, and hypercholesterolemia. Current treatment for PAD involves lifestyle and symptom management, statin and antiplatelet therapy, and/or surgical interventions to improve quality of life with varying efficacy. PAD affects approximately 5 to 6 percent of the global population, with this global burden continuing to increase. Despite the increase in disease prevalence, no gold standard functional diagnostic tool has been established for enabling early detection of the disease, appropriate medical management, and prediction of adverse outcomes for PAD patients. The visualization and quantification of the physiological consequences of PAD are possible by way of nuclear imaging: specifically, via scintigraphy, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) imaging. These non-invasive modalities, when combined with targeted radionuclides, possess utility for detecting functional perfusion deficits and provide unique insight into muscle tissue- and vascular-level characteristics of PAD patients. This review discusses the past, present, and emerging applications of hybrid nuclear imaging modalities in the evaluation and monitoring of patients with PAD.

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.

Objective: Peripheral artery disease (PAD) is associated with increased risk of nonhealing ulcers, amputation, and mortality due to occlusive atherosclerotic plaques. Computed tomography (CT) imaging detects vascular calcification in PAD; however, quantitative vessel-by-vessel analysis of calcium burden in the feet of PAD patients has not been assessed. This study sought to perform quantitative analysis of vessel-specific calcium burden and examine the patient-level determinants of foot calcium burden in PAD patients. Approach: PAD patients ( n  = 41) were prospectively enrolled and underwent CT imaging of the lower extremities. Manual segmentation of the medial plantar, lateral plantar, and dorsalis pedis arteries was performed. CT image Hounsfield units (HUs) were obtained for each artery to quantify vessel-by-vessel calcium mass using a cutoff value of ≥130 HU. Univariate analyses were performed to evaluate patient-level determinants of calcium burden for each foot artery. STROBE guidelines were used for reporting of data. Results: Univariate analyses revealed that body mass index, diabetes mellitus (DM), and chronic kidney disease (CKD) were significant determinants of foot calcium burden in PAD patients. Image analysis demonstrated that PAD patients with DM had significantly higher calcium mass for the medial plantar ( p  = 0.005), lateral plantar ( p  = 0.039), and dorsalis pedis ( p  = 0.001) arteries compared with PAD patients without DM. Innovation: This is the first study to use CT imaging to quantify vessel-specific calcium burden in the feet of patients with PAD and evaluate the patient-level determinants of foot calcium burden in the setting of PAD. Conclusion: CT imaging quantifies vessel-specific calcification in the feet of PAD patients, which is exacerbated with concomitant DM, CKD, and/or obesity.

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).)