ABSTRACT
PURPOSE: To determine the relationship between the American College of Cardiology/American Heart Association (ACC/AHA) risk score and plaque phenotype of the coronary and carotid arteries assessed directly using CT angiography and MRI. MATERIALS AND METHODS: Asymptomatic subjects eligible for statin therapy by risk score were enrolled in a prospective study of disease burden using coronary artery calcium (CAC) scoring, coronary CT angiography, and MRI of the carotid arteries. Quartiles were calculated for noncalcified plaque, CAC, and average carotid wall volume and were compared with ACC/AHA risk quartiles. RESULTS: Two hundred three subjects were studied (60% men; mean age, 65 years). There were weak correlations between risk and carotid wall volume (Kendall tau = 0.29), noncalcified plaque (tau = 0.16), and CAC (tau = 0.33). ACC/AHA risk alone misclassified plaque extent compared with measurement by carotid wall volume, CAC, and noncalcified plaque in 22.1%, 24.1%, and 29.6% of subjects, respectively. On average, 13% of the subjects were underclassified, and 12.5% were overclassified. CONCLUSION: Approximately 25% of subjects had large discrepancies between ACC/AHA risk and plaque burden at imaging. These results suggest that clinical risk score models alone do not fully reflect the amount of atherosclerotic disease present.© RSNA, 2020See also the commentary by Truong and Villines in this issue.
ABSTRACT
Transplantation-based replacement of lost and/or dysfunctional astrocytes is a promising therapy for spinal cord injury (SCI) that has not been extensively explored, despite the integral roles played by astrocytes in the central nervous system (CNS). Induced pluripotent stem (iPS) cells are a clinically-relevant source of pluripotent cells that both avoid ethical issues of embryonic stem cells and allow for homogeneous derivation of mature cell types in large quantities, potentially in an autologous fashion. Despite their promise, the iPS cell field is in its infancy with respect to evaluating in vivo graft integration and therapeutic efficacy in SCI models. Astrocytes express the major glutamate transporter, GLT1, which is responsible for the vast majority of glutamate uptake in spinal cord. Following SCI, compromised GLT1 expression/function can increase susceptibility to excitotoxicity. We therefore evaluated intraspinal transplantation of human iPS cell-derived astrocytes (hIPSAs) following cervical contusion SCI as a novel strategy for reconstituting GLT1 expression and for protecting diaphragmatic respiratory neural circuitry. Transplant-derived cells showed robust long-term survival post-injection and efficiently differentiated into astrocytes in injured spinal cord of both immunesuppressed mice and rats. However, the majority of transplant-derived astrocytes did not express high levels of GLT1, particularly at early times post-injection. To enhance their ability to modulate extracellular glutamate levels, we engineered hIPSAs with lentivirus to constitutively express GLT1. Overexpression significantly increased GLT1 protein and functional GLT1-mediated glutamate uptake levels in hIPSAs both in vitro and in vivo post-transplantation. Compared to human fibroblast control and unmodified hIPSA transplantation, GLT1-overexpressing hIPSAs reduced (1) lesion size within the injured cervical spinal cord, (2) morphological denervation by respiratory phrenic motor neurons at the diaphragm neuromuscular junction, and (3) functional diaphragm denervation as measured by recording of spontaneous EMGs and evoked compound muscle action potentials. Our findings demonstrate that hiPSA transplantation is a therapeutically-powerful approach for SCI.
