Burden of heart failure in Asia, 1990-2019: findings from the Global Burden of Disease Study 2019.

OBJECTIVES: Heart failure (HF) is on the rise as a global health problem, but information on its burden in Asia is limited. This study aimed to assess the burden, trends, and underlying causes of HF in the Asian region. STUDY DESIGN AND METHODS: Data on HF in Asia from 1990 to 2019, including prevalence, years lived with disability (YLD), and underlying causes, were extracted from the Global Burden of Diseases 2019. The cases, the age-standardized prevalence, and the YLD were compared between the age groups, the sexes, the sociodemographic index, and the locations. The proportion of age-standardized prevalence rates of HF attributable to 16 underlying causes was also analyzed. RESULTS: In 2019, the age-standardized prevalence rate of HF per 100,000 persons in Asia was 722.45 (95% uncertainty interval [UI]: 591.97-891.64), with an estimated 31.89 million cases (95% UI: 25.94-39.25). From 1990 to 2019, the prevalence of age-standardized HF in Asia decreased by 4.51%, reflecting the global trend (-7.06%). Age-standardized YLD rates of HF exhibited patterns similar to prevalence rates. Among Asian countries, China had the highest age-standardized prevalence rate, followed by Kuwait and Jordan. Hypertensive heart disease was the leading cause of HF, followed by ischemic heart disease and rheumatic heart disease. CONCLUSIONS: Although the burden of HF in Asia showed a gradual decline between 1990 and 2019, it remains a significant health challenge that requires increased attention. Regional disparities in HF burden are evident, emphasizing the need for urgent prevention and control measures at the regional and national levels.

ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer.

OBJECTIVE: Cisplatin (CDDP)-based chemotherapy is a first-line, drug regimen for muscle-invasive bladder cancer (BC) and metastatic bladder cancer. Clinically, resistance to CDDP restricts the clinical benefit of some bladder cancer patients. AT-rich interaction domain 1A (ARID1A) gene mutation occurs frequently in bladder cancer; however, the role of CDDP sensitivity in BC has not been studied. METHODS: We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology. IC50 determination, flow cytometry analysis of apoptosis, and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A. qRT-PCR, Western blotting, RNA interference, bioinformatic analysis, and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC. RESULTS: It was found that ARID1A inactivation was associated with CDDP resistance in BC cells. Mechanically, loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3 (EIF4A3) through epigenetic regulation. Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399 (circ0008399), a novel circular RNA (circRNA) identified in our previous study, which, to some extent, showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells. Importantly, EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP. CONCLUSION: Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.

Simultaneous Quantification of Methotrexate and Its Metabolite 7-Hydroxy-Methotrexate in Human Plasma for Therapeutic Drug Monitoring.

OBJECTIVE: To establish and validate a simple, sensitive, and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the determination of methotrexate (MTX) and its major metabolite 7-hydroxy-methotrexate (7-OH-MTX) in human plasma. METHOD: The chromatographic separation was achieved on a Zorbax C18 column (3.5 µm, 2.1 × 100 mm) using a gradient elution with methanol (phase B) and 0.2% formic acid aqueous solution (phase A). The flow rate was 0.3 mL/min with analytical time of 3.5 min. Mass spectrometry detection was performed in a triple-quadruple tandem mass spectrometer under positive ion mode with the following mass transitions: m/z 455.1/308.1 for MTX, 471.0/324.1 for 7-OH-MTX, and 458.2/311.1 for internal standard. The pretreatment procedure was optimized with dilution after one-step protein precipitation. RESULTS: The calibration range of methotrexate and 7-OH-MTX was 5.0-10000.0 ng/mL. The intraday and interday precision and accuracy were less than 15% and within ±15% for both analytes. The recovery for MTX and 7-OH-MTX was more than 90% and the matrix effect ranged from 97.90% to 117.60%. CONCLUSION: The method was successfully developed and applied to the routine therapeutic drug monitoring of MTX and 7-OH-MTX in human plasma.

Role of Jagged1-Hey1 Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis.

BACKGROUND: Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy. METHODS: Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg-1·min-1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT), a γ-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg·kg-1·d-1. Forty mice were divided into four groups (n = 10 per group): control group; Ang II group, treated with Ang II; DAPT group, treated with DAPT; and Ang II + DAPT group, treated with both Ang II and DAPT. At the end of experiments, myocardial (left ventricle [LV]) tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test. RESULTS: Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin (HE) staining and immunohistochemistry for CD31, a vascular marker (P < 0.05 for both). Meanwhile, Jagged1 protein was significantly increased, but gene expression for both Jag1 and Hey1 was decreased in the LV following Ang II treatment, compared to that in controls (relative ratio for Jag1 gene: 0.45 ± 0.13 vs. 0.84 ± 0.15; relative ratio for Hey1 gene: 0.51 ± 0.08 vs. 0.91 ± 0.09; P < 0.05). All these cellular and molecular effects induced by Ang II in the hearts of mice were reduced by DAPT treatment. Interestingly, Ang II stimulated Hey1, a known Notch target, but did not affect the expression of Hey2, another Notch target gene. CONCLUSIONS: A Jagged1-Hey1 signal might mediate the impairment of angiogenesis induced by Ang II during cardiac hypertrophy.

Plasma nesfatin-1 level in obese patients after acupuncture: a randomised controlled trial.

BACKGROUND: Nesfatin-1 is an anorexigenic hormone suggested to regulate obesity. OBJECTIVE: To investigate the relationship between nesfatin-1 level and anthropometric and metabolic parameters in obese patients, and examine the change in plasma nesfatin-1 level after acupuncture treatment. METHODS: 64 obese adult patients without diabetes and 58 normal weight control subjects were enrolled in this study. The obese patients were randomly divided into an acupuncture plus diet group (n=32) and a diet only group (n=32). Measurements were repeated after 45 days. RESULTS: Body mass index (BMI), waist and hip circumferences, serum insulin, lipoprotein and insulin resistance measures were significantly higher, and plasma nesfatin-1 level was significantly lower, in obese patients than in normal weight controls. In addition, negative correlations were found between plasma nesfatin-1 level and BMI, waist and hip circumferences. Weight reduction in participants after acupuncture and diet restriction was 7.0% and 4.3%, respectively. Plasma nesfatin-1 level increased from 2.75±1.16 to 3.44±1.28 ng/mL and from 2.86±1.07 to 3.23±1.06 ng/mL in acupuncture and diet groups, respectively; the difference was significant, p<0.05. CONCLUSIONS: Plasma nesfatin-1 level is reduced in obese adults, and is increased after acupuncture. The beneficial effect of acupuncture on obesity is associated with increased plasma nesfatin-1 level.

Decreased plasma nesfatin-1 levels in patients with acute myocardial infarction.

Nesfatin-1 is a novel anorexigenic hormone which has close relationship with diabetes, obese, anorexia nervosa, psychiatric disorders and neurogenic diseases. The aim of our study was to evaluate levels of plasma nesfatin-1 among patients presenting with coronary artery disease and the correlation between nesfatin-1 levels and other clinical parameters. Fasting plasma levels of nesfatin-1 were tested in 48 acute myocardial infarction (AMI) patients, 74 stable angina pectoris (SAP) patients and 34 control subjects. All of them were examined by coronary angiography. The severity of coronary atherosclerosis was assessed using the Gensini score. Plasma nesfatin-1 levels were significantly lower in AMI group than SAP group or control group (0.91±0.08 ng/mL vs. 0.98±0.19 ng/mL and 1.09±0.39 ng/mL, respectively, P<0.05). In AMI patients, plasma nesfatin-1 levels were negatively correlated with high-sensitivity C-reactive protein, neutrophil% or Gensini scores. Such information implies that lower nesfatin-1 concentration may play a very important role in the development of AMI.

SORCS1 and APOE polymorphisms interact to confer risk for late-onset Alzheimer's disease in a Northern Han Chinese population.

Sortilin-related VPS domain containing receptor 1 (SORCS1), is located on chromosome 10q23.3, a chromosomal region of interest in Alzheimer's disease (AD) defined by many genome-wide and chromosome10-specific studies. Recently, three intronic variants (rs12571141, rs17277986 and rs6584777) within SORCS1 were reported to be associated with AD in Caucasian. In order to assess the involvement of the SORCS1 polymorphisms in the progression of late-onset AD (LOAD), we conducted an independent replication study in 1198 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 600 healthy controls matched for gender and age. The results revealed no significant differences in the distributions of genotype or allele between LOAD and control groups in the total sample. However, when these data were stratified by the Apolipoprotein E (APOE) ε4 status, we observed significant differences in the genotypes and allele frequencies (rs12571141: P=0.001, rs17277986: P=0.005, rs6584777: P=0.023) in APOE ε4 allele carriers. Moreover, the association was further demonstrated in logistic regression analysis (rs12571141: P=0.002, OR=0.424; rs17277986: P=0.004, OR=0.447; rs6584777: P=0.019, OR=0.523) and haplotype analysis (GCC: P=0.002, ATT: P=0.002, ACC: P=0.025) in this subset. Our data suggested that SORCS1 was in interaction with APOE in the development of LOAD in a Northern Han Chinese population.