Spectral analysis of non-contrast fluoroscopy for evaluation of pulmonary perfusion: Feasibility and sensitivity testing with a phantom.

BACKGROUND: Oscillating x-ray attenuation in the lungs provides an opportunity to evaluate pulmonary perfusion without contrast. Recent intensity-based methods have been compared to pulmonary scintigraphy and CT angiography but lack rigorous phantom studies. PURPOSE: A new method to quantify the periodic signal amplitude was employed using spectral analysis. Performance was characterized using a water phantom capable of creating an oscillating x-ray attenuation at physiologic amplitudes. Feasibility in detecting abnormal perfusion was performed on a volunteer with pulmonary vascular disease and compared to pulmonary angiography, the clinical gold standard. METHODS: For each fluoroscopic acquisition, the normalized temporal signal from each pixel was decomposed into its frequency components using Fourier transformation, and the spectral amplitude, defined as the x-ray pulsatility index (XPI), was determined at the desired frequency using a band-pass filter. XPI was displayed as a pixel-wise parametric colormap. Based on XPI maps generated using two human volunteers, a water bath phantom was constructed with a fluctuating fluid height and a 1 cm diameter pulsatility defect. Contrast-to-noise (CNR) of the defect was measured using fluoroscopy images acquired at variable fluid height fluctuation (0.1-1.9 mm) and oscillation frequency (30-60 bpm). Various sampling frame rates (3-30 fps) and acquisition durations (1.8-8 s) using truncated datasets were reconstructed from full datasets. Fluoroscopic images were obtained in a patient just prior to pulmonary angiography in the same projection. RESULTS: XPI maps in human subjects showed high signal to background contrast with high central XPI measuring up to 0.5. Phantom experiments revealed CNR was linearly correlated to fluid height change (r2  = 0.998). CNR is proportional to increasing sampling frame rate and increasing acquisition duration as expected with Fourier analysis. XPI map displayed multifocal perfusion defects in good agreement with pulmonary angiography. CONCLUSION: Spectral analysis is an accurate and sensitive method to detect small changes in periodic x-ray attenuation using a short fluoroscopic acquisition. This method demonstrated good agreement to pulmonary angiography and shows promise for clinical imaging of pulmonary perfusion using standard fluoroscopic methods.

Design and Rationale for the Direct Oral Anticoagulant Apixaban in Left Ventricular Assist Devices (DOAC LVAD) Study.

Implantable left ventricular assist device (LVAD) therapy is used to improve quality of life, alleviate symptoms and extend survival rates in patients with advanced heart failure. Patients with LVADs require chronic anticoagulation to reduce the risk of thromboembolic complications, and they commonly experience bleeding events. Apixaban is a direct oral anticoagulant that has become first-line therapy for patients with nonvalvular atrial fibrillation and venous thromboembolism; however, its safety in patients with LVADs has not been well characterized. The evaluation of the hemocompatibility in the DOAC LVAD (Direct Oral Anti-Coagulant apixaban in Left Ventricular Assist Devices) trial is a phase 2, open-label trial of patients with LVADs who were randomized to either apixaban or warfarin therapy. Patients randomized to apixaban will be started on a dosage of 5 mg twice daily, whereas those randomized to warfarin will be managed at an International Normalized Ratio goal of 2.0-2.5. All patients will be treated with aspirin at 81 mg daily. We plan to randomize and follow as many as 40 patients for 24 weeks to evaluate the primary outcomes of freedom from death or hemocompatibility-related adverse events (stroke, device thrombosis, bleeding, aortic root thrombus, and arterial non-CNS thromboembolism). The DOAC LVAD trial will establish the feasibility of apixaban anticoagulant therapy in patients with LVADs. Clinicaltrials.gov: NCT04865978.

Effect of Statin Intensity on the Progression of Cardiac Allograft Vasculopathy.

Background: In the non-transplant population, hyperlipidaemia has shifted from targeting LDL goals to statin intensity-based treatment. It is unknown whether this strategy is also beneficial in cardiac transplantation. Methods: This single-centre retrospective study evaluated the effect of statin use and intensity on time to cardiac allograft vasculopathy (CAV) after cardiac transplantation. Kaplan-Meier and Cox proportional hazards regression survival methods were used to assess the association of statin intensity and median post-transplant LDL on CAV-free survival. Results: The study involved 143 adults (71% men, average follow-up of 25 ± 14 months) who underwent transplant between 2013 and 2017. Mean CAV-free survival was 47.5 months (95% CI [43.1-51.8]), with 29 patients having CAV grade 1 or greater. Median LDL was not associated with time to CAV (p=0.790). CAV-free survival did not differ between intensity groups (p=0.435). Conclusion: Given the non-statistically significant difference in time to CAV with higher intensity statins, the data suggest that advancing moderate- or high-intensity statin after cardiac transplantation may not provide additional long-term clinical benefit. Trial registration: Not applicable.

Up-regulation of ATP binding cassette transporter A1 expression by very low density lipoprotein receptor and apolipoprotein E receptor 2.

Activation of very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (apoER2) results in either pro- or anti-atherogenic effects depending on the ligand. Using reelin and apoE as ligands, we studied the impact of VLDLR- and apoER2-mediated signaling on the expression of ATP binding cassette transporter A1 (ABCA1) and cholesterol efflux using RAW264.7 cells. Treatment of these mouse macrophages with reelin or human apoE3 significantly increased ABCA1 mRNA and protein levels, and apoAI-mediated cholesterol efflux. In addition, both reelin and apoE3 significantly increased phosphorylated disabled-1 (Dab1), phosphatidylinositol 3-kinase (PI3K), protein kinase Cζ (PKCζ), and specificity protein 1 (Sp1). This reelin- or apoER2-mediated up-regulation of ABCA1 expression was suppressed by 1) knockdown of Dab1, VLDLR, and apoER2 with small interfering RNAs (siRNAs), 2) inhibition of PI3K and PKC with kinase inhibitors, 3) overexpression of kinase-dead PKCζ, and 4) inhibition of Sp1 DNA binding with mithramycin A. Activation of the Dab1-PI3K signaling pathway has been implicated in VLDLR- and apoER2-mediated cellular functions, whereas the PI3K-PKCζ-Sp1 signaling cascade has been implicated in the regulation of ABCA1 expression induced by apoE/apoB-carrying lipoproteins. Taken together, these data support a model in which activation of VLDLR and apoER2 by reelin and apoE induces ABCA1 expression and cholesterol efflux via a Dab1-PI3K-PKCζ-Sp1 signaling cascade.