Flexible 3-D Electrochemical Impedance Spectroscopy Sensors Incorporating Phase Delay for Comprehensive Characterization of Atherosclerosis

Distinguishing quiescent from rupture-prone atherosclerotic lesions has significant translational and clinical implications. Electrochemical impedance spectroscopy (EIS) characterizes biological tissues by assessing impedance and phase delay responses to alternating current at multiple frequencies.We evaluated invasive 6-point stretchable EIS sensors over a spectrum of experimental atherosclerosis and compared results with intravascular ultrasound (IVUS), molecular positron emission tomography (PET) imaging, and histology.Male New Zealand White rabbits (n=16) were placed on a high-fat diet for 4 or 8 weeks, with or without endothelial denudation via balloon injury of the infrarenal abdominal aorta. Rabbits underwent in vivo micro-PET imaging of the abdominal aorta with 68 Ga-DOTATATE, 18 F-NaF, and 18 F-FDG, followed by invasive interrogation via IVUS and EIS. Background signal corrected values of impedance and phase delay were determined. Abdominal aortic samples were collected for histological analyses. Analyses were performed blindly.Phase delay correlated with anatomic markers of plaque burden, namely intima/media ratio (r=0.883 at 1 kHz, P =0.004) and %stenosis (r=0.901 at 0.25 kHz, P =0.002), similar to IVUS. Moreover, impedance was associated with markers of plaque activity including macrophage infiltration (r=0.813 at 10 kHz, P =0.008) and macrophage/smooth muscle cell (SMC) ratio (r=0.813 at 25 kHz, P =0.026). 68 Ga-DOTATATE correlated with intimal macrophage infiltration (r=0.861, P =0.003) and macrophage/SMC ratio (r=0.831, P =0.021), 18 F-NaF with SMC infiltration (r=-0.842, P =0.018), and 18 F-FDG correlated with macrophage/SMC ratio (r=0.787, P =0.036).EIS with phase delay integrates key atherosclerosis features that otherwise require multiple complementary invasive and non-invasive imaging approaches to capture. These findings indicate the potential of invasive EIS as a comprehensive modality for evaluation of human coronary artery disease.Electrochemical impedance spectroscopy (EIS) characterizes both anatomic features - via phase delay; and inflammatory activity - via impedance profiles, of underlying atherosclerosis.EIS can serve as an integrated, comprehensive metric for atherosclerosis evaluation by capturing morphological and compositional plaque characteristics that otherwise require multiple imaging modalities to obtain.Translation of these findings from animal models to human coronary artery disease may provide an additional strategy to help guide clinical management.