Agreement of ejection fraction measured by coronary computed tomography (CT) and cardiac ultrasound in evaluating patients with chronic heart failure: an observational comparative study.

Background: Cardiac ultrasound is one of the most important examinations in cardiovascular medicine, but the technical requirements for the operator are relatively high, which to some extent affects the scope of its use. This study was dedicated to investigating the agreement of ejection fraction between coronary computed tomography (CT) and cardiac ultrasound and diagnostic performance in evaluating the clinical diagnosis of patients with chronic heart failure. Methods: We conducted a single-center-based retrospective study including 343 consecutive patients enrolled between January 2019 to April 2020, all of whom presented with suspected symptoms of heart failure within one month. All enrolled cases performed cardiac ultrasound and coronary CT scans. The CT images were analyzed using accurate left ventricle (AccuLV) artificial intelligence (AI) software to calculate the ejection fraction-computed tomography (EF-CT) and it was compared with the ejection fraction (EF) obtained based on ultrasound. Cardiac insufficiency was determined if the EF measured by ultrasound was below 50%. Diagnostic performance analysis, correlation analysis and Bland-Altman plot were used to compare agreement between EF-CT and CT. Results: Of the 319 successfully performed patients, 220 (69%) were identified as cardiac insufficiency. Quantitative consistency analysis showed a good correlation between EF-CT and EF values in all cases (R square =0.704, r=0.837). Bland-Altman analysis showed mean bias of 6.6%, mean percentage error of 27.5% and 95% limit of agreement of -17% to 30% between EF and EF-CT. The results of the qualitative diagnostic study showed that the sensitivity and specificity of EF measured by coronary CT reached a high level of 91% [95% confidence interval (CI): 86-94%], and the positive diagnostic value was up to 96% (95% CI: 92-98%). Conclusions: The EF-CT and EF have excellent agreement, and AccuLV-based AI left ventricular function analysis software perhaps can be used as a clinical diagnostic reference.

YAP at the Crossroads of Biomechanics and Drug Resistance in Human Cancer.

Biomechanical forces are of fundamental importance in biology, diseases, and medicine. Mechanobiology is an emerging interdisciplinary field that studies how biological mechanisms are regulated by biomechanical forces and how physical principles can be leveraged to innovate new therapeutic strategies. This article reviews state-of-the-art mechanobiology knowledge about the yes-associated protein (YAP), a key mechanosensitive protein, and its roles in the development of drug resistance in human cancer. Specifically, the article discusses three topics: how YAP is mechanically regulated in living cells; the molecular mechanobiology mechanisms by which YAP, along with other functional pathways, influences drug resistance of cancer cells (particularly lung cancer cells); and finally, how the mechanical regulation of YAP can influence drug resistance and vice versa. By integrating these topics, we present a unified framework that has the potential to bring theoretical insights into the design of novel mechanomedicines and advance next-generation cancer therapies to suppress tumor progression and metastasis.

Impact of Baseline Bleeding Risk on Efficacy and Safety of Ticagrelor versus Clopidogrel in Chinese Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

BACKGROUND: There was still conflict on the antithrombotic advantage of ticagrelor versus clopidogrel among East Asian population with acute coronary syndrome (ACS). We considered that the baseline bleeding risk might be an undetected key factor that significantly affected the efficacy of ticagrelor. METHODS: A total of 20,816 serial patients who underwent percutaneous coronary intervention (PCI) from October 2011 to August 2014 in the General Hospital of Shenyang Military Region were enrolled in the present study. Patients receiving ticagrelor or clopidogrel were further subdivided according to basic bleeding risk. The primary outcome was net adverse clinical events (NACEs) defined as major adverse cardiac or cerebral events (MACCE, including all-cause death, myocardial infarction, ischemia-driven target vessel revascularization, or stroke) and any bleeding during 1-year follow-up. Comparison between ticagrelor and clopidogrel was adjusted by propensity score matching (PSM). RESULTS: Among the 20,816 eligible PCI patients who were included in this study, there were 1578 and 779 patients in the clopidogrel and ticagrelor groups, respectively, after PSM, their clinical parameters were well matched. Patients receiving ticagrelor showed comparable NACE risk compared with those treated by clopidogrel (5.3% vs. 5.1%, P = 0.842). Furthermore, ticagrelor might reduce the MACCE risk in patients with low bleeding risk but increase MACCE in patients with moderate-to-high bleeding potential (ticagrelor vs. clopidogrel, low bleeding risk: 2.5% vs. 4.9%, P = 0.022; moderate-to-high bleeding risk: 4.8% vs. 3.0%, P = 0.225; interaction P = 0.021), with vast differences in all bleeding (low bleeding risk: 1.5% vs. 0.8%, P = 0.210; moderate-to-high bleeding risk: 4.8% vs. 3.0%, P = 0.002; interaction P = 0.296). CONCLUSION: Among real-world Chinese patients with ACS treated by PCI, ticagrelor only showed superior efficacy in patients with low bleeding risk but lost its advantage in patients with moderate-to-high bleeding potential.

Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease.

BACKGROUND: Pivotal clinical trials found that ticagrelor reduced ischaemic complications to a greater extent than clopidogrel, and also that the benefit gradually increased with the reduction in creatinine clearance. However, the underlying mechanisms remains poorly explored. METHODS: This was a single-centre, prospective, randomized clinical trial involving 60 hospitalized Adenosine Diphosphate (ADP) P2Y12 receptor inhibitor-naïve patients with chronic kidney disease (CKD) (estimated glomerular filtration rate <60 ml min-1 1.73 m-2 ) and non-ST-elevation acute coronary syndromes (NSTE-ACS). Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180 mg loading dose, then followed by 90 mg twice daily) or clopidogrel (600 mg loading dose, then followed by 75 mg once daily). The primary endpoint was the P2Y12 reactive unit (PRU) value assessed by VerifyNow at 30 days. The plasma concentrations of ticagrelor and clopidogrel and their active metabolites were measured in the first 10 patients in each group at baseline, and at 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after the loading dose. RESULTS: Baseline characteristics were well matched between the two groups. Our results indicated a markedly lower PRU in patients treated with ticagrelor vs. clopidogrel at 30 days (32.6 ± 11.29 vs. 203.7 ± 17.92; P < 0.001) as well as at 2 h, 8 h and 24 h after the loading dose (P < 0.001). Ticagrelor and its active metabolite AR-C124910XX showed a similar time to reach maximum concentration (Cmax ) of 8 h, with the maximum concentration (Cmax ) of 355 (242.50-522.00) ng ml-1 and 63.20 (50.80-85.15) ng ml-1 , respectively. Both clopidogrel and its active metabolite approached the Cmax at 2 h, with a similar Cmax of 8.67 (6.64-27.75) ng ml-1 vs. 8.53 (6.94-15.93) ng ml-1 . CONCLUSION: Ticagrelor showed much more potent platelet inhibition in comparison with clopidogrel in patients with CKD and NSTE-ACS.

HNF-4alpha Negatively Regulates Hepcidin Expression Through BMPR1A in HepG2 Cells.

Hepcidin synthesis is reported to be inadequate according to the body iron store in patients with non-alcoholic fatty liver disease (NAFLD) undergoing hepatic iron overload (HIO). However, the underlying mechanisms remain unclear. We hypothesize that hepatocyte nuclear factor-4α (HNF-4α) may negatively regulate hepcidin expression and contribute to hepcidin deficiency in NAFLD patients. The effect of HNF-4α on hepcidin expression was observed by transfecting specific HNF-4α small interfering RNA (siRNA) or plasmids into HepG2 cells. Both direct and indirect mechanisms involved in the regulation of HNF-4α on hepcidin were detected by real-time PCR, Western blotting, chromatin immunoprecipitation (chIP), and reporter genes. It was found that HNF-4α suppressed hepcidin messenger RNA (mRNA) and protein expressions in HepG2 cells, and this suppressive effect was independent of the potential HNF-4α response elements. Phosphorylation of SMAD1 but not STAT3 was inactivated by HNF-4α, and the SMAD4 response element was found essential to HNF-4α-induced hepcidin reduction. Neither inhibitory SMADs, SMAD6, and SMAD7 nor BMPR ligands, BMP2, BMP4, BMP6, and BMP7 were regulated by HNF-4α in HepG2 cells. BMPR1A, but not BMPR1B, BMPR2, ActR2A, ActR2B, or HJV, was decreased by HNF-4α, and HNF4α-knockdown-induced stimulation of hepcidin could be entirely blocked when BMPR1A was interfered with at the same time. In conclusion, the present study suggests that HNF-4α has a suppressive effect on hepcidin expression by inactivating the BMP pathway, specifically via BMPR1A, in HepG2 cells.

Hyperinsulinemia induces hepatic iron overload by increasing liver TFR1 via the PI3K/IRP2 pathway.

Dysmetabolic iron overload syndrome (DIOS) is frequently observed, but the underlying mechanism remains unclear. We propose the hypothesis that hyperinsulinemia, a common characteristic of DIOS, may stimulate liver transferrin receptor 1 (TFR1) expression via the PI3K/iron regulatory protein 2 (IRP2) pathway, leading to the occurrence of DIOS. The hepatic iron content, serum iron parameters, and expressions of TFRs and IRPs in the liver were determined in rats with temporary or long-lasting hyperinsulinemia induced by acute or chronic administration of insulin. The effect of insulin on TFR1 expression and its molecular mechanism were determined in HL-7702 cells in vitro. It was found that long-lasting hyperinsulinemia significantly increased TFR1 expression in the liver and induced mild-to-moderate hepatic iron overload, which was accompanied by a normal level of serum iron. Insulin markedly upregulated both protein and mRNA levels of TFR1 in HL-7702 cells. The stability of TFR1 mRNA stability, together with expression of IRPs expression, were both significantly increased by insulin treatment. Insulin-induced TFR1 expression was blocked by IRP2, but not by IRP1 interference, and disappeared when HL-7702 cells were pretreated with LY294002, triciribine hydrate, or rapamycin. In conclusion, the findings of this study indicate that hyperinsulnemia could induce hepatic iron overload by upregulating liver TFR1 via the PI3K/AKT/mTOR/IRP2 pathway, which may be one of the main reasons for the occurrence of DIOS.

Hepcidin is directly regulated by insulin and plays an important role in iron overload in streptozotocin-induced diabetic rats.

Iron overload is frequently observed in type 2 diabetes mellitus (DM2), but the underlying mechanisms remain unclear. We hypothesize that hepcidin may be directly regulated by insulin and play an important role in iron overload in DM2. We therefore examined the hepatic iron content, serum iron parameters, intestinal iron absorption, and liver hepcidin expression in rats treated with streptozotocin (STZ), which was given alone or after insulin resistance induced by a high-fat diet. The direct effect of insulin on hepcidin and its molecular mechanisms were furthermore determined in vitro in HepG2 cells. STZ administration caused a significant reduction in liver hepcidin level and a marked increase in intestinal iron absorption and serum and hepatic iron content. Insulin obviously upregulated hepcidin expression in HepG2 cells and enhanced signal transducer and activator of transcription 3 protein synthesis and DNA binding activity. The effect of insulin on hepcidin disappeared when the signal transducer and activator of transcription 3 pathway was blocked and could be partially inhibited by U0126. In conclusion, the current study suggests that hepcidin can be directly regulated by insulin, and the suppressed liver hepcidin synthesis may be an important reason for the iron overload in DM2.

Glucocorticoid causes iron accumulation in liver by up-regulating expression of iron regulatory protein 1 gene through GR and STAT5.

Iron regulatory protein-1 (IRP-1) is a central factor in the regulation of iron metabolism. Stress causes elevated glucocorticoid secretion and is also associated with iron accumulation in liver; however, the relation between these two processes is not known. Whether glucocorticoids alter the expression of liver IRP-1 and if this contributes to the iron accumulation is presently investigated. Administration (i.v.) of corticosterone daily to rats for 7 days resulted in the upregulation of IRP-1 and transferrin receptor-1 and accumulation of iron in liver. However, expression of ferritin was decreased. The effects of corticosterone were reduced by the prior administration of glucocorticoid antagonist, RU486 to the rats. Similarly, in vitro studies using HL7702 liver cells showed that hydrocortisone increases the expression of IRP-1 while decreasing ferritin. It is also observed that Stat-5 phosphorylation is enhanced in HL7702 cells by hydrocortisone. The electrophoretic mobility shift assays revealed that the binding of glucocorticoid receptor and phospho-STAT5 to the promoter region of IRP-1 gene was enhanced in rats of stress group. Combination of both RU486 and STAT5 inhibitor, PIAS resulted in a stronger reduction of IRP-1 expression than when these inhibitors were used separately. These results strongly implicate glucocorticoid receptor and STAT5 in stress-induced up-regulation of IRP-1, which subsequently enhances transferrin receptor-1 expression and down-regulates ferritin, causing iron accumulation in the liver.