Efficacy of pharmacological and interventional treatment for resistant hypertension: a network meta-analysis.

AIMS: Resistant hypertension is associated with a high risk of cardiovascular disease, chronic kidney disease, and mortality. Yet, its management is challenging. This study aims to establish the comparative effectiveness of pharmacologic and interventional treatments by conducting a network meta-analysis. METHODS AND RESULTS: MEDLINE, Cochrane Register of Controlled Trials, and Web of Science Core Collection were systematically searched in March 2022. Randomized controlled trials comparing treatment options for management of resistant hypertension were included. Outcomes were blood pressure (BP) changes, measured in the office and in 24 h ambulatory BP measurement. We applied a frequentist random effects model to perform a network meta-analysis combining placebo medication and sham procedure as the reference comparator. From 4771 records, 24 studies met the inclusion criteria with 3458 included patients in total. Twelve active treatment alternatives [spironolactone, doxazosin, ß-blocker, clonidine, darusentan, guanfacine, various types of renal sympathetic denervation, lifestyle intervention, continuous positive airway pressure, and baroreflex activation therapy (BAT)] were analysed. Among all comparators, spironolactone had the highest ranking probability and was considered the most effective treatment to reduce office systolic blood pressure (sBP) [-13.30 mmHg (-17.89; -8.72); P < 0.0001] and 24 h sBP [-8.46 mmHg (-12.54; -4.38); P < 0.0001] in patients with resistant hypertension. Lifestyle interventions were the most effective non-pharmacological treatment, lowering office sBP by -7.26 mmHg (-13.73; -0.8), whereas BAT lowered office sBP by -7.0 (-18.59; 4.59). Renal denervation lowered office sBP by -5.64 mmHg (-12.95; 1.66) and -3.79 mmHg (-11.39; 3.8) depending on the type of the procedure. CONCLUSION: Among all pharmacologic and interventional treatments, spironolactone is the most effective treatment in reducing BP in patients with resistant hypertension. More comparative trials and especially trials with long-term follow-up are needed. In the meanwhile, we have to conclude that a combination of spironolactone and lifestyle modification are the most effective treatments in resistant hypertension.

Myocardial Characterization with Extracellular Volume Mapping with a First-Generation Photon-counting Detector CT with MRI Reference.

Background Photon-counting detector (PCD) CT provides comprehensive spectral data with every acquisition, but studies evaluating myocardial extracellular volume (ECV) quantification with use of PCD CT compared with an MRI reference remain lacking. Purpose To compare ECV quantification for myocardial tissue characterization between a first-generation PCD CT system and cardiac MRI. Materials and Methods In this single-center prospective study, adults without contraindication to iodine-based contrast media underwent same-day cardiac PCD CT and MRI with native and postcontrast T1 mapping and late gadolinium enhancement for various clinical indications for cardiac MRI (the reference standard) between July 2021 and January 2022. Global and midventricular ECV were assessed with use of three methods: single-energy PCD CT, dual-energy PCD CT, and MRI T1 mapping. Quantitative comparisons among all techniques were performed. Correlation and reliability between different methods of ECV quantification were assessed with use of the Pearson correlation coefficient (r) and the intraclass correlation coefficient. Results The final sample included 29 study participants (mean age ± SD, 54 years ± 17; 15 men). There was a strong correlation of ECV between dual- and single-energy PCD CT (r = 0.91, P < .001). Radiation dose was 40% lower with dual-energy versus single-energy PCD CT (volume CT dose index, 10.1 mGy vs 16.8 mGy, respectively; P < .001). In comparison with MRI, dual-energy PCD CT showed strong correlation (r = 0.82 and 0.91, both P < .001) and good to excellent reliability (intraclass correlation coefficients, 0.81 and 0.90) for midventricular and global ECV quantification, but it overestimated ECV by approximately 2%. Single-energy PCD CT showed similar relationship with MRI but underestimated ECV by 3%. Conclusion Myocardial tissue characterization with photon-counting detector CT-based quantitative extracellular volume analysis showed a strong correlation to MRI. © RSNA, 2023 Supplemental material is available for this article.

Coronary Computed Tomography Angiography-Based Calcium Scoring: In Vitro and In Vivo Validation of a Novel Virtual Noniodine Reconstruction Algorithm on a Clinical, First-Generation Dual-Source Photon Counting-Detector System.

PURPOSE: The aim of this study was to evaluate coronary computed tomography angiography (CCTA)-based in vitro and in vivo coronary artery calcium scoring (CACS) using a novel virtual noniodine reconstruction (PureCalcium) on a clinical first-generation photon-counting detector-computed tomography system compared with virtual noncontrast (VNC) reconstructions and true noncontrast (TNC) acquisitions. MATERIALS AND METHODS: Although CACS and CCTA are well-established techniques for the assessment of coronary artery disease, they are complementary acquisitions, translating into increased scan time and patient radiation dose. Hence, accurate CACS derived from a single CCTA acquisition would be highly desirable. In this study, CACS based on PureCalcium, VNC, and TNC, reconstructions was evaluated in a CACS phantom and in 67 patients (70 [59/80] years, 58.2% male) undergoing CCTA on a first-generation photon counting detector-computed tomography system. Coronary artery calcium scores were quantified for the 3 reconstructions and compared using Wilcoxon test. Agreement was evaluated by Pearson and Spearman correlation and Bland-Altman analysis. Classification of coronary artery calcium score categories (0, 1-10, 11-100, 101-400, and >400) was compared using Cohen κ . RESULTS: Phantom studies demonstrated strong agreement between CACS PureCalcium and CACS TNC (60.7 ± 90.6 vs 67.3 ± 88.3, P = 0.01, r = 0.98, intraclass correlation [ICC] = 0.98; mean bias, 6.6; limits of agreement [LoA], -39.8/26.6), whereas CACS VNC showed a significant underestimation (42.4 ± 75.3 vs 67.3 ± 88.3, P < 0.001, r = 0.94, ICC = 0.89; mean bias, 24.9; LoA, -87.1/37.2). In vivo comparison confirmed a high correlation but revealed an underestimation of CACS PureCalcium (169.3 [0.7/969.4] vs 232.2 [26.5/1112.2], P < 0.001, r = 0.97, ICC = 0.98; mean bias, -113.5; LoA, -470.2/243.2). In comparison, CACS VNC showed a similarly high correlation, but a substantially larger underestimation (24.3 [0/272.3] vs 232.2 [26.5/1112.2], P < 0.001, r = 0.97, ICC = 0.54; mean bias, -551.6; LoA, -2037.5/934.4). CACS PureCalcium showed superior agreement of CACS classification ( κ = 0.88) than CACS VNC ( κ = 0.60). CONCLUSIONS: The accuracy of CACS quantification and classification based on PureCalcium reconstructions of CCTA outperforms CACS derived from VNC reconstructions.

Dual-Energy CT Perfusion of Invasive Tumor Front in Non-Small Cell Lung Cancers.

Background Active endothelial cell proliferation occurs at the tumor edge, known as the invading-tumor front. This study focused on perfusion analysis of non-small cell lung cancers. Purpose To analyze dual-phase, dual-energy CT perfusion according to the degree of tumor hypoxia. Materials and Methods This prospective study was performed 2016-2017. A two-phase dual-energy CT protocol was obtained for consecutive participants with operable non-small cell lung cancer. The first pass and delayed iodine concentration within the tumor and normalized iodine uptake, corresponding to the iodine concentration within the tumor normalized to iodine concentration within the aorta, were calculated for the entire tumor and within three peripheral layers automatically segmented (ie, 2-mm-thick concentric subvolumes). The expression of the membranous carbonic anhydrase (mCA) IX, a marker of tumor hypoxia, was assessed in tumor specimens. Comparative analyses according to the histologic subtypes, type of resected tumors, and mCA IX expression were performed. Results There were 33 mCA IX-positive tumors and 16 mCA IX-negative tumors. In the entire tumor, the mean normalized iodine uptake was higher on delayed than on first-pass acquisitions (0.35 ± 0.17 vs 0.13 ± 0.15, respectively; P < .001). A single layer, located at the edge of the tumor, showed higher values of the iodine concentration (median, 0.53 mg/mL vs 0.21 mg/mL, respectively; P = .03) and normalized iodine uptake (0.04 vs 0.02, respectively; P = .03) at first pass in mCA IX-positive versus mCA IX-negative tumors. Within this layer, a functional profile of neovascularization was found in 23 of 33 (70%) of mCA IX-positive tumors, and the median mCA IX score of these tumors was higher than in tumors with a nonfunctional profile of neovascularization (median mCA IX score, 20 vs 2, respectively; P = .03). Conclusion A two-phase dual-energy CT examination depicted higher perfusion between the tumor edge and lung parenchyma in hypoxic tumors. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Murphy and Ryan in this issue.

First Clinical Photon-counting Detector CT System: Technical Evaluation.

Background The first clinical CT system to use photon-counting detector (PCD) technology has become available for patient care. Purpose To assess the technical performance of the PCD CT system with use of phantoms and representative participant examinations. Materials and Methods Institutional review board approval and written informed consent from four participants were obtained. Technical performance of a dual-source PCD CT system was measured for standard and high-spatial-resolution (HR) collimations. Noise power spectrum, modulation transfer function, section sensitivity profile, iodine CT number accuracy in virtual monoenergetic images (VMIs), and iodine concentration accuracy were measured. Four participants were enrolled (between May 2021 and August 2021) in this prospective study and scanned using similar or lower radiation doses as their respective clinical examinations performed on the same day using energy-integrating detector (EID) CT. Image quality and findings from the participants' PCD CT and EID CT examinations were compared. Results All standard technical performance measures met accreditation and regulatory requirements. Relative to filtered back-projection reconstructions, images from iterative reconstruction had lower noise magnitude but preserved noise power spectrum shape and peak frequency. Maximum in-plane spatial resolutions of 125 and 208 µm were measured for HR and standard PCD CT scans, respectively. Minimum values for section sensitivity profile full width at half maximum measurements were 0.34 mm (0.2-mm nominal section thickness) and 0.64 mm (0.4-mm nominal section thickness) for HR and standard PCD CT scans, respectively. In a 120-kV standard PCD CT scan of a 40-cm phantom, VMI iodine CT numbers had a mean percentage error of 5.7%, and iodine concentration had root mean squared error of 0.5 mg/cm3, similar to previously reported values for EID CT. VMIs, iodine maps, and virtual noncontrast images were created for a coronary CT angiogram acquired with 66-msec temporal resolution. Participant PCD CT images showed up to 47% lower noise and/or improved spatial resolution compared with EID CT. Conclusion Technical performance of clinical photon-counting detector (PCD) CT is improved relative to that of a current state-of-the-art CT system. The dual-source PCD geometry facilitated 66-msec temporal resolution multienergy cardiac imaging. Study participant images illustrated the effect of the improved technical performance. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Willemink and Grist in this issue.

Bone Mineral Density Quantification from Localizer Radiographs: Accuracy and Precision of Energy-integrating Detector CT and Photon-counting Detector CT.

Background Bone mineral density (BMD) could be derived from CT localizer radiographs and could potentially enable opportunistic osteoporosis screening. Purpose To assess the accuracy and precision of BMD measurement using two localizer radiographs obtained with energy-integrating detector CT and a single localizer radiograph obtained with photon-counting detector CT. Materials and Methods A calibration phantom and a porcine phantom with lumbar vertebrae were imaged with a dual-energy x-ray absorptiometry (DXA) scanner, a clinical energy-integrating detector CT scanner, and a prototype photon-counting detector CT scanner. Two localizer radiographs at different combinations of tube voltages were obtained with energy-integrating detector CT, and one localizer radiograph was obtained with photon-counting detector CT using different energy thresholds. BMD was calculated for all three approaches and compared with the known specifications in the calibration phantom. In the animal phantom, BMDs from both CT systems were compared with those from the DXA scanner (the reference standard). Accuracy was defined as the measurement error of BMD (ΔBMD), and precision was defined as the coefficient of variation (in percentage). Radiation doses were estimated. Nonparametric tests were applied. Results In the calibration phantom, ΔBMD was smaller with both CT systems compared with the DXA scanner (both P < .05). ΔBMD ranged from -5% to -1.8% for DXA, from -2.3% to -1.7% for energy-integrating detector CT, and from -1.6% to 1.6% for photon-counting detector CT. Precision (range, 0.3%-2.8%) was high for both CT systems. In the animal phantom, ΔBMD ranged from -0.6% to 0.1% for energy-integrating detector CT and from -0.1% to 0.6% for photon-counting detector CT, with no significant differences between CT systems (P = .65). The dose-area product in the animal phantom was 4.6 cGy ∙ cm2 for DXA, 3.5-11.5 cGy ∙ cm2 for energy-integrating detector CT, and 7.2-11.2 cGy ∙ cm2 for photon-counting detector CT, depending on tube voltage and energy threshold combination. Conclusion Experimental evidence suggests that bone mineral density measurements are accurate and precise using two localizer radiographs at different tube voltages from energy-integrating detector CT and a single localizer radiograph with different energy thresholds from photon-counting detector CT. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Pourmorteza in this issue.

Correlation of Iodine Quantification and FDG Uptake in Early Therapy Response Assessment of Non-small Cell Lung Cancer: Possible Benefit of Dual-energy CT Scan as an Integral Part of PET/CT Examination.

AIM: To compare iodine-related and fluorine-18 fluorodeoxyglucose (18F-FDG) parameters during staging of lung cancer as well as during early follow-up, while investigating potential use and possible substitutability in the assessment of therapeutic response or prediction. PATIENTS AND METHODS: Patients (n=45) with confirmed lung cancer underwent 18F-FDG positron-emission tomography (PET) using single-source dual-energy computed tomography was performed for staging and early follow-up. Correlation of FDG uptake and iodine-related parameters was assessed and comparison with therapy response was performed. RESULTS: A strong correlation was found between the volumetric FDG parameters metabolic tumour volume (MTV) and total lesion glycolysis (TLG) and iodine uptake (IU) in staging (IU vs. MTV: rs=0.894; p<0.001 and IU vs. TLG: rs=0.874; p<0.001) and follow-up (IU vs. MTV: rs=0.934, p<0.001 and IU vs. TLG: rs=0.935, p<0.001). We also found significant correlation of change in these values between timepoints. We observed a significant correlation of IU, MTV and TLG with early therapy response and IU was found as a possible strong predictor. CONCLUSION: Strong correlation of IU and volume-based FDG parameters was proved in staging, follow-up and change during therapy. Potential role of IU in prediction of early therapy-response was identified. Our study suggests a significant benefit of using the dual-energy computed tomography as a part of 18F-FDG PET/CT in patients with lung cancer.

Quantitative therapy response assessment by volumetric iodine-uptake measurement: initial experience in patients with advanced hepatocellular carcinoma treated with sorafenib.

OBJECTIVES: To investigate the volumetric iodine-uptake (VIU) changes by dual-energy CT (DECT) in assessing the response to sorafenib treated hepatocellular carcinoma (HCC) patients, compared with AASLD (American Association for the Study of Liver Diseases) and Choi criteria. MATERIALS AND METHODS: Fifteen patients with HCC receiving sorafenib, monitored with contrast-enhanced DECT scans at baseline and a minimum of one follow-up (8-12 weeks) were retrospectively evaluated. 30 target lesions in total were analyzed for tumor response according to VIU and adapted Choi criteria and compared with the standard AASLD. RESULTS: According to AASLD criteria, 67% target lesions showed disease control: partial response (PR) in 3% and stable disease (SD) in 63%. 33% lesions progressed (PD). Disease control rate presented by VIU (60%) was similar to AASLD (67%) and Choi (63%) (P>0.05). For disease control group, change in mean VIU was from 149.5 ± 338.3mg to 108.5 ± 284.1mg (decreased 19.1 ± 42.9%); and for progressive disease group, change in mean VIU was from 163.7 ± 346.7 mg to 263.9 ± 537.2 mg (increased 230.5 ± 253.1%). Compared to AASLD (PR, 3%), VIU and Choi presented more PR (33% and 30%, respectively) in disease control group (P<0.05). VIU has moderate consistency with both AASLD (kappa=0.714; P<0.005) and Choi (kappa=0.648; P<0.005), while VIU showed a better consistency and correlation with AASLD (kappa=0.714; P<0.005; r=0.666, P<0.005) than Choi with AASLD (kappa=0.634, P<0.005; r=0.102, P=0.296). CONCLUSION: VIU measurements by DECT can evaluate the disease control consistent with the current standard AASLD. Measurements are semi-automatic and therefore easy and robust to apply. As VIU reflects vital tumor burden in HCC, it is likely to be an optimal tumor response biomarker in HCC.

Expression, localization, structural, and functional characterization of pFGE, the paralog of the Calpha-formylglycine-generating enzyme.

pFGE is the paralog of the formylglycine-generating enzyme (FGE), which catalyzes the oxidation of a specific cysteine to Calpha-formylglycine, the catalytic residue in the active site of sulfatases. The enzymatic activity of sulfatases depends on this posttranslational modification, and the genetic defect of FGE causes multiple sulfatase deficiency. The structural and functional properties of pFGE were analyzed. The comparison with FGE demonstrates that both share a tissue-specific expression pattern and the localization in the lumen of the endoplasmic reticulum. Both are retained in the endoplasmic reticulum by a saturable mechanism. Limited proteolytic cleavage at similar sites indicates that both also share a similar three-dimensional structure. pFGE, however, is lacking the formylglycine-generating activity of FGE. Although overexpression of FGE stimulates the generation of catalytically active sulfatases, overexpression of pFGE has an inhibitory effect. In vitro pFGE interacts with sulfatase-derived peptides but not with FGE. The inhibitory effect of pFGE on the generation of active sulfatases may therefore be caused by a competition of pFGE and FGE for newly synthesized sulfatase polypeptides.

Molecular characterization of the human Calpha-formylglycine-generating enzyme.

Calpha-formylglycine (FGly) is the catalytic residue in the active site of sulfatases. In eukaryotes, it is generated in the endoplasmic reticulum by post-translational modification of a conserved cysteine residue. The FGly-generating enzyme (FGE), performing this modification, is an endoplasmic reticulum-resident enzyme that upon overexpression is secreted. Recombinant FGE was purified from cells and secretions to homogeneity. Intracellular FGE contains a high mannose type N-glycan, which is processed to the complex type in secreted FGE. Secreted FGE shows partial N-terminal trimming up to residue 73 without loosing catalytic activity. FGE is a calcium-binding protein containing an N-terminal (residues 86-168) and a C-terminal (residues 178-374) protease-resistant domain. The latter is stabilized by three disulfide bridges arranged in a clamp-like manner, which links the third to the eighth, the fourth to the seventh, and the fifth to the sixth cysteine residue. The innermost cysteine pair is partially reduced. The first two cysteine residues are located in the sequence preceding the N-terminal protease-resistant domain. They can form intramolecular or intermolecular disulfide bonds, the latter stabilizing homodimers. The C-terminal domain comprises the substrate binding site, as evidenced by yeast two-hybrid interaction assays and photocross-linking of a substrate peptide to proline 182. Peptides derived from all known human sulfatases served as substrates for purified FGE indicating that FGE is sufficient to modify all sulfatases of the same species.

Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme.

C(alpha)-formylglycine (FGly) is the catalytic residue in the active site of eukaryotic sulfatases. It is posttranslationally generated from a cysteine in the endoplasmic reticulum. The genetic defect of FGly formation causes multiple sulfatase deficiency (MSD), a lysosomal storage disorder. We purified the FGly generating enzyme (FGE) and identified its gene and nine mutations in seven MSD patients. In patient fibroblasts, the activity of sulfatases is partially restored by transduction of FGE encoding cDNA, but not by cDNA carrying an MSD mutation. The gene encoding FGE is highly conserved among pro- and eukaryotes and has a paralog of unknown function in vertebrates. FGE is localized in the endoplasmic reticulum and is predicted to have a tripartite domain structure.