New objective simple evaluation methods of amyloid PET/CT using whole-brain histogram and Top20%-Map.

OBJECTIVE: This study aims to assess the utility of newly developed objective methods for the evaluation of intracranial abnormal amyloid deposition using PET/CT histogram without use of cortical ROI analyses. METHODS: Twenty-five healthy volunteers (HV) and 38 patients with diagnosed or suspected dementia who had undergone 18F-FPYBF-2 PET/CT were retrospectively included in this study. Out of them, 11C-PiB PET/CT had been also performed in 13 subjects. In addition to the conventional methods, namely visual judgment and quantitative analyses using composed standardized uptake value ratio (comSUVR), the PET images were also evaluated by the following new parameters: the skewness and the mode-to-mean ratio (MMR) obtained from the histogram of the brain parenchyma; Top20%-map highlights the areas with high tracer accumulation occupying 20% volume of the total brain parenchymal on the individual's CT images. We evaluated the utility of the new methods using histogram compared with the visual assessment and comSUVR. The results of these new methods between 18F-FPYBF-2 and 11C-PiB were also compared in 13 subjects. RESULTS: In visual analysis, 32, 9, and 22 subjects showed negative, border, and positive results, and composed SUVR in each group were 1.11 ± 0.06, 1.20 ± 0.13, and 1.48 ± 0.18 (p < 0.0001), respectively. Visually positive subjects showed significantly low skewness and high MMR (p < 0.0001), and the Top20%-Map showed the presence or absence of abnormal deposits clearly. In comparison between the two tracers, visual evaluation was all consistent, and the ComSUVR, the skewness, the MMR showed significant good correlation. The Top20%-Maps showed similar pattern. CONCLUSIONS: Our new methods using the histogram of the brain parenchymal accumulation are simple and suitable for clinical practice of amyloid PET, and Top20%-Map on the individual's brain CT can be of great help for the visual assessment.

Crosstalk between oxygen signaling and iron metabolism in renal interstitial fibroblasts.

To maintain the oxygen supply, the production of red blood cells (erythrocytes) is promoted under low-oxygen conditions (hypoxia). Oxygen is carried by hemoglobin in erythrocytes, in which the majority of the essential element iron in the body is contained. Because iron metabolism is strictly controlled in a semi-closed recycling system to protect cells from oxidative stress caused by iron, hypoxia-inducible erythropoiesis is closely coordinated by regulatory systems that mobilize stored iron for hemoglobin synthesis. The erythroid growth factor erythropoietin (EPO) is mainly secreted by interstitial fibroblasts in the renal cortex, which are known as renal EPO-producing (REP) cells, and promotes erythropoiesis and iron mobilization. Intriguingly, EPO production is strongly induced by hypoxia through iron-dependent pathways in REP cells. Here, we summarize recent studies on the network mechanisms linking hypoxia-inducible EPO production, erythropoiesis and iron metabolism. Additionally, we introduce disease mechanisms related to disorders in the network mediated by REP cell functions. Furthermore, we propose future studies regarding the application of renal cells derived from the urine of kidney disease patients to investigate the molecular pathology of chronic kidney disease and develop precise and personalized medicine for kidney disease.

PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity.

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.

The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction.

AIMS: Kidney disease often leads to anemia due to a defect in the renal production of the erythroid growth factor erythropoietin (EPO), which is produced under the positive regulation of hypoxia-inducible transcription factors (HIFs). Chemical compounds that inhibit HIF-prolyl hydroxylases (HIF-PHs), which suppress HIFs, have been developed to reactivate renal EPO production in renal anemia patients. Currently, multiple HIF-PH inhibitors, in addition to conventional recombinant EPO reagents, are used for renal anemia treatment. This study aimed to elucidate the therapeutic mechanisms and drug-specific properties of HIF-PH inhibitors. METHODS AND KEY FINDINGS: Gene expression analyses and mass spectrometry revealed that HIF-PH inhibitors (daprodustat, enarodustat, molidustat, and vadadustat) alter Epo gene expression levels in the kidney and liver in a drug-specific manner, with different pharmacokinetics in the plasma and urine after oral administration to mice. The drug specificity revealed the dominant contribution of EPO induction in the kidneys rather than in the liver to plasma EPO levels after HIF-PH inhibitor administration. We also found that several HIF-PH inhibitors directly induce duodenal gene expression related to iron intake, while these drugs indirectly suppress hepatic hepcidin expression to mobilize stored iron for hemoglobin synthesis through induction of the EPO-erythroferrone axis. SIGNIFICANCE: Renal EPO induction is the major target of HIF-PH inhibitors for their therapeutic effects on erythropoiesis. Additionally, the drug-specific properties of HIF-PH inhibitors in EPO induction and iron metabolism have been shown in mice, providing useful information for selecting the proper HIF-PH inhibitor for each renal anemia patient.

CORRIGENDUM: Preprocedural Controlling Nutritional Status Score as a Predictor of Mortality in Patients Undergoing Transcatheter Mitral Valve Repair　- A Single Center Experience in Japan.

[This corrects the article DOI: 10.1253/circrep.CR-23-0055.].

Newer versus Early Generation of the MitraClip for Primary Mitral Regurgitation: A Japanese Single-Center Experience.

Background: The MitraClip G4 system is the latest version of the transcatheter edge-to-edge repair (TEER) system for mitral regurgitation (MR). We aimed to investigate the impact of the new system on routine clinical practice and patient outcomes in the treatment of primary MR. Methods: Consecutive patients with primary MR who underwent TEER with either the MitraClip G2 or G4 between 2018 and 2021 were enrolled from a single center registry. Baseline clinical and echocardiographic characteristics as well as procedural and clinical outcomes up to 1 year were compared between groups. Technical and device success were defined in accordance with the Mitral Valve Academic Research Consortium criteria. Results: Among 71 patients with primary MR, 34 were treated with G2 and 37 were treated with G4. Patients treated with G4 had lower surgical risk (7.74 [5.04, 14.97] vs. 5.26 [3.98, 6.40]; p < 0.01) than those with G2. There were no significant differences in other baseline clinical variables between groups. On baseline echocardiography, MR volume and flail gap were significantly greater in the G4 group than in the G2 group (regurgitant volume: 63 [41-76] mL vs. 68 [62-84] mL; p = 0.04, flail gap: 4.5 [3.5-5.5] mm vs. 5.4 [4.5-7.1] mm; p = 0.04). Technical success was achieved in over 95% of both groups with no significant difference (p > 0.99). Device success was achieved in 61.8% of the G2 group, while in 70.3% of the G4 group (p = 0.47). Post-procedural MR severity was comparable (p = 0.42) and there was no significant difference in the occurrence of mitral stenosis (p = 0.61) between groups. Among patients who reached 1-year follow-up (n = 54), there was no significant difference between groups in a composite endpoint of death or heart failure rehospitalization (10.5% vs. 20.2%; HR 0.61; 95% CI 0.17-2.22; p = 0.45). Residual heart failure symptoms (NYHA ≥ 3) at 1 year were observed in 3.7% of the G2 group, while no patient in the G4 group (p > 0.99). Conclusions: The MitraClip G4 system achieved comparable device outcomes to the early-generation device (G2), despite treating more severe primary MR with a larger flail gap.