The association between composite dietary antioxidant index and diabetic retinopathy in type 2 diabetic patients: evidence from the NHANES.

Background: Although diabetic retinopathy (DR) is closely related to dietary patterns and oxidative stress, there is little research on the relationship between the compound dietary antioxidant index (CDAI) and DR. This study aims to fill this gap by analyzing data from the National Health and Nutrition Examination Survey (NHANES) to explore the association between CDAI and DR in patients with type 2 diabetes, in order to provide a basis for dietary guidance to prevent DR. Methods: Data for this study was obtained from NHANES conducted between 1999 and 2020. Information regarding dietary intake was collected through 24 h dietary recall interviews. Multivariate logistic regression analyses and restricted cubic splines (RCS) were employed to explore the association between CDAI and DR. Furthermore, subgroup analyses were conducted to further examine the relationship. Results: In this study, a total of 2,158 participants were included, with a mean age of 58.87 years. After adjusting for all potential confounding factors, multivariate logistic regression analyses consistently demonstrated a negative correlation between CDAI and DR (OR = 0.94, 95%CI: 0.90-0.98, p = 0.007). Specifically, individuals in the highest quartile of CDAI had a significantly reduced risk of DR compared to those in the lowest quartile (OR = 0.51, 95%CI: 0.34-0.75, p < 0.001). The RCS analyses further confirmed the linear negative correlation between CDAI and DR (non-linear p = 0.101). Additionally, subgroup analyses provided further evidence for the robustness of this association across different subpopulations. Conclusion: Our study highlights the linear negative correlation between CDAI and DR in type 2 diabetic patients. Further prospective studies are still needed in the future to confirm the role of CDAI in the risk of developing DR.

U-shaped association between serum Klotho and all-cause mortality in US cardiovascular patients: a prospective cohort study.

Background: Increased levels of serum Klotho have been associated with a reduced risk of several cardiovascular diseases (CVD). However, limited studies exist on the association between serum Klotho and mortality in patients with CVD. Methods: We collected data from CVD patients in the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2016. We linked NHANES data with the National Death Index to determine the survival status of participants. Univariate and multivariable Cox regression models were used to investigate the relationship between serum Klotho levels and mortality in CVD patients. The relationship between serum Klotho quartiles and mortality in CVD patients was visualized using Kaplan-Meier (KM) curves and restricted cubic spine. Finally, subgroup analyses were used to examine the association between serum Klotho and all-cause mortality in different populations. Results: 1905 patients with CVD were finally enrolled in our study with a mean follow-up of 7.1 years. The average age of the participants was 63.4 years, with 58.40% being male. KM showed that lower Klotho levels were associated with lower survival rates. After adjusting for potential confounders, patients with higher serum Klotho levels had lower all-cause mortality (Q1: 1.00, Q2: 0.58 (0.42-0.80), Q3: 0.69 (0.47-1.01), and Q4:0.64 (0.45-0.92). However, the relationship between serum Klotho levels and cardiovascular mortality was not statistically significant. Dose-response analysis shows a U-shaped relationship between serum Klotho levels and all-cause mortality in patients with CVD (P nonlinear=0.002). Subgroup analysis indicated that participants with a history of hypertension had a higher risk of all-cause mortality in serum Klotho Q4 compared to Q1 (P trend <0.05). Conclusion: The relationship between serum Klotho levels and all-cause mortality in CVD patients exhibits a U-shaped association. The underlying mechanisms of this association need further investigation.

Association between life's essential 8 and biological ageing among US adults.

BACKGROUND: Biological ageing is tightly linked to cardiovascular disease (CVD). We aimed to investigate the relationship between Life's Essential 8 (LE8), a currently updated measure of cardiovascular health (CVH), and biological ageing. METHODS: This cross-sectional study selected adults ≥ 20 years of age from the 2005-2010 National Health and Nutrition Examination Survey. LE8 scores (range 0-100) were obtained from measurements based on American Heart Association definitions, divided into health behavior and health factor scores. Biological ageing was assessed by different methods including phenotypic age, phenotypic age acceleration (PhenoAgeAccel), biological age and biological age acceleration (BioAgeAccel). Correlations were analyzed by weighted linear regression and restricted cubic spline models. RESULTS: Of the 11,729 participants included, the mean age was 47.41 ± 0.36 years and 5983 (51.01%) were female. The mean phenotypic and biological ages were 42.96 ± 0.41 and 46.75 ± 0.39 years, respectively, and the mean LE8 score was 67.71 ± 0.35. After adjusting for potential confounders, higher LE8 scores were associated with lower phenotypic age, biological age, PhenoAgeAccel, and BioAgeAccel, with nonlinear dose-response relationships. Negative associations were also found between health behavior and health factor scores and biological ageing, and were stronger for health factors. In health factor-specific analyses, the ß negativity was greater for blood glucose and blood pressure. The inverse correlations of LE8 scores with phenotypic age and biological age in the stratified analyses remained solid across strata. CONCLUSIONS: LE8 and its subscale scores were strongly negatively related to biological ageing. Encouraging optimal CVH levels may be advantageous in preventing and slowing down ageing.

Circulating levels of cytokines and risk of cardiovascular disease: a Mendelian randomization study.

Background: Epidemiological studies have linked various circulating cytokines to cardiovascular disease (CVD), which however remains uncertain whether these relationships represent causality or are due to bias. To address this question, we conducted a Mendelian randomization (MR) analysis to systematically investigate the causal effects of circulating cytokine levels on CVD development. Methods: This study leveraged the summary statistic from respective genome-wide association study (GWAS) of 47 cytokines and four types of CVD. The cis-quantitative trait locus (cis-QTL) definition, derived from a GWAS meta-analysis comprising 31,112 participants of European descent, served as instruments for cytokines. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. Results: The results of inverse-variance weighted method using cis-protein QTL (cis-pQTL) instruments, showed the causal effects of four cytokines (i.e., IL-1ra, MCSF, SeSelectin, SCF) on the risk of coronary artery disease (CAD). We also identified causal relationships between two cytokines (i.e., IL-2ra, IP-10) and heart failure (HF), as well as two cytokines (i.e., MCP-3, SeSelectin) and atrial fibrillation (AF), after controlling for false discovery rate (FDR). The use of cis-expression QTL (cis-eQTL) revealed additional causal associations between IL-1a, MIF and CAD, between IL-6, MIF, and HF, as well as between FGFBasic and AF. No significant sign was survived for stroke with FDR applied. Results were largely consistent across sensitivity analyses. Conclusion: The present study provides supportive evidence that genetic predisposition to levels of certain cytokines causally affects the development of specific type of CVD. These findings have important implications for the creation of novel therapeutic strategies targeting these cytokines as a means of preventing and treating CVD.

Vericiguat for the Treatment of Heart Failure with Reduced Ejection Fraction Following a Worsening Heart Failure Event: A Cost-Effectiveness Analysis from the Perspective of Chinese Healthcare Providers.

BACKGROUND AND OBJECTIVE: Approximately 38 million people worldwide experience heart failure (HF), with more than 10 million in China. Heart failure exacerbations are the main cause of HF hospitalization, and hospitalizations are the main driver of HF-associated costs. Vericiguat is recommended to treat patients who have had worsening HF despite guideline-directed medical therapy. However, the cost effectiveness of adding vericiguat to the standard treatment of this population in China remains unclear. The objective of this study was to investigate the cost effectiveness of adding vericiguat to standard treatment in patients with HF in the Chinese population METHODS: A lifetime Markov model with a 1-month cycle length was developed to compare the cost effectiveness of vericiguat plus standard treatment versus standard treatment alone in Chinese patients with HF with reduced ejection fraction following an HF exacerbation, from the perspective of Chinese healthcare providers. The clinical data were obtained from the VICTORIA study. The cost was accessed from our institution or studies conducted in China. The primary outcome was the incremental cost-effectiveness ratio, representing incremental cost per incremental quality-adjusted life-year (QALY). Vericiguat was considered highly cost effective if the incremental cost-effectiveness ratio obtained was lower than 12,551 USD/QALY, cost effective if the incremental cost-effectiveness ratio was between 12,551 and 37,654.5 USD/QALY, and not cost effective if the incremental cost-effectiveness ratio was higher than 37,654.5 USD/QALY. A scenario analysis, one-way sensitivity analysis, and probabilistic sensitivity analysis were performed to test the robustness of the results. RESULTS: For a 67-year-old patient with HF following an HF exacerbation, the lifetime cost was 17,721 USD if vericiguat plus standard treatment was given, compared to 7907 USD if standard treatment alone was prescribed. The corresponding effectiveness was 2.20 QALY and 2.10 QALY, respectively. The incremental cost-effectiveness ratio of vericiguat plus standard treatment versus standard treatment alone in Chinese patients with HF was 89,429 USD/QALY, higher than the willingness-to-pay threshold of 37654.5 USD/QALY. The scenario analysis and sensitivity analysis showed the robustness of our results. CONCLUSIONS: The addition of vericiguat to the treatment regimen of Chinese patients with HF with reduced ejection fraction following an HF exacerbation resulted in an incremental cost-effectiveness ratio of $89,429 USD/QALY compared to standard treatment. This incremental cost-effectiveness ratio exceeds the willingness-to-pay threshold and thus, vericiguat was deemed not cost effective in the Chinese population.

Causality of telomere length associated with calcific aortic valvular stenosis: A Mendelian randomization study.

Background: Observational studies have shown that calcific aortic valve stenosis (CAVS) is associated with a shorter telomere length (TL). However, the results of observational studies are often influenced by confounding factors and reverse causal associations; it is unclear whether there is a causal relationship between TL and CAVS. This study aimed to investigate the causal relationship between TL and CAVS. Materials and methods: Genome-wide association study (GWAS) data on TL (n = 472,174) and CAVS (n = 311,437) were used to assess the effect of TL on CAVS. All the participants were of European ancestry. Three Mendelian randomization (MR) methods, namely, MR-Egger, weighted median, and inverse variance weighted (IVW), were used to assess the potential causal effect of TL on CAVS. Heterogeneity was assessed using Cochran's Q statistic. Leave-one-out and MR-Egger regression methods were used for sensitivity and pleiotropy analyses. Forward and reverse MR analyses were performed. Results: In total, 118 valid and independent TL genetic instrumental variants were extracted from the GWAS dataset. MR analysis showed that TL was negatively associated with CAVS (odds ratios [OR] = 0.727, 95% confidence interval [CI]: 0.565-0.936, and P = 0.013 by weighted median; OR = 0.763, 95% CI: 0.634-0.920, and P = 0.005 by IVW; OR = 0.757, 95% CI: 0.549-1.044, and P = 0.055 by MR-Egger). Sensitivity and pleiotropy analyses showed that the results of this study were relatively stable and that there was no significant pleiotropy. Reverse MR analyses consistently suggested the absence of causal effects of CAVS liability on TL levels. Conclusion: A causal relationship between the shortening of TL and the development of CAVS in the European population was suggested in this study, and a theoretical basis was provided to investigate the pathogenesis of CAVS.

Patients with Earlobe Crease May Associate with Lower Concentration of the Age-Suppressing Hormone Klotho.

OBJECTIVE: Earlobe crease (ELC) has been considered as a skin sign of atherosclerosis, and its pathophysiological mechanism is still unclear. Our study aims to test the hypothesis that ELC patients with lower serum levels of the age-suppressing hormone Klotho, which is not only associated with premature aging but also with endothelial dysfunction, may be associated with atherosclerosis. METHODS: A total of 135 patients aged 40-68 years underwent coronary angiography. According to the presence or absence of coronary heart disease (CAD) and ELC, they were divided into three groups: CAD group and ELC group (ELC group, n = 45); no ELC group (non-ELC group, n = 45). There was no ELC or CAD in the control group (control group, n = 45). Serum Klotho concentration was obtained by enzyme-linked immunosorbent assay (ELISA). RESULTS: The Klotho level in the ELC group was 365.6 ± 38.1 pg/mL, while the Klotho level in the non-ELC group was 568.8 ± 44.9 pg/mL. It is worth noting that the Klotho level of the ELC group was significantly lower than that of the non-ELC group (P < 0.001). The serum Klotho level of the control group was higher than that of the non-ELC group (593.3±45.3 vs 568.8±44.9 pg/mL, P = 0.702), but the difference was not statistically significant. Multiple logistic regression analysis showed that the Klotho level is a parameter that affects the appearance of ELC. CONCLUSION: Serum Klotho levels were considerably lower in patients with ELC. We concluded that the perturbations of Klotho in patients might be associated with ELC and with CAD.

Adropin and Irisin Deficiencies Are Associated With Presence of Diagonal Earlobe Crease in CAD Patients.

Background and Aims: Diagonal earlobe crease (ELC) has been considered a potential cutaneous marker of atherosclerosis. However, the potential mechanism by which ELC and atherosclerosis are linked has not been adequately defined. Roles of adropin and irisin, novel biomarkers of endothelial function, in ELC have not been well-studied. This study aimed to test whether individuals with ELC are deficient in adropin and irisin, a characteristic that would likely promote endothelial dysfunction and provide a plausible common pathological basis for atherosclerosis and ELC. Methods: Patients diagnosed with coronary artery disease (CAD) with (n = 45) and without (n = 45) ELC were consecutively enrolled in the study. The ages of the patients enrolled ranged from 40-70 years. Other patients (n = 45) without ELC or CAD were recruited as the control group. All patients underwent coronary angiography. Serum adropin and irisin concentrations were assessed via enzyme-linked immunosorbent assay. Results: Circulating levels of irisin in the ELC group were significantly lower than those in the non-ELC group, and were highest in the control group. Serum adropin levels of the ELC group were significantly lower than those of the non-ELC group (P < 0.001). Interestingly, although the serum adropin level of the control group was greater than that of the non-ELC group, the difference failed to achieve statistical significance. In subgroup analysis of CAD and ELC, both serum adropin and irisin levels of the CAD and ELC groups were lower than those of the control group (P < 0.001). Receiver-operating characteristic curve analysis revealed that adropin and irisin have similar prognostic power for CAD and ELC. Conclusions: Low adropin and irisin were significantly associated with CAD and ELC. The deficiencies in adropin and irisin may be a common cause of both atherosclerosis and ELC, which explains why patients with ELC are prone to CAD.

Saikosaponin-d Suppresses COX2 Through p-STAT3/C/EBPß Signaling Pathway in Liver Cancer: A Novel Mechanism of Action.

Saikosaponin-d (SSd) is an active extract from Radix Bupleuri, the dried root from the plant Bupleurum falcatum used in China for thousands of years to treat liver diseases. The SSd extract possesses valuable pharmacological activities including anti-cancer and anti-inflammatory effects; however, the mechanism underlying the anti-cancer activity of SSd is largely unknown. Here, we explored the mechanism of action of SSd as an anti-cancer agent for liver cancer in two human hepatocellular carcinoma cell lines. Using MTT and annexin-V-FITC/PI assays, Western blots, immunohistochemistry, qRT-PCR, luciferase reporter assay, and a JAK2-specific inhibitor (AG490), we demonstrated that the anti-tumorigenic effects of SSd act through the intermediatory p-STAT3/C/EBPß signaling pathway to suppress cyclooxygenase (COX)-2. SSd effectively inhibited cell proliferation in a dose-dependent manner. Apoptosis was significantly increased in cells treated with SSd (2.5-15 µg/ml) with concurrent increase and decrease in pro- and anti-apoptosis proteins, respectively. COX-2, C/EBPß, and p-STAT3 were significantly decreased, at both the translational and transcriptional levels, by SSd treatment. AG490 produced similar inhibitory effects on STAT3, p-STAT3, C/EBPß, and COX-2. In conclusion, our data suggest that SSd controls liver cancer proliferation through suppression of the p-STAT3/C/EBPß signaling pathway inhibiting COX2 expression. These findings further our understanding of the pharmacological action of SSd, providing new information on SSd mechanism of action and showing potential for SSd as a novel therapy for liver cancer.

A rare cause of sudden dyspnea and unexpected death in adolescence: fistula from aortic sinus of Valsalva to right atrium.

Aneurysm of the sinus of Valsalva is a rare cardiac abnormality. Unruptured sinus of Valsalva aneurysm is usually asymptomatic, however, a ruptured aneurysm typically leads to an aortocardiac shunt and progressively worsening heart failure. We report a case of a 17-year-old male who suffered an aneurysm of the sinus of Valsalva rupture into the right atrium who manifested sudden dyspnea and acute heart failure.

Saikosaponin­d suppresses the expression of cyclooxygenase­2 through the phospho­signal transducer and activator of transcription 3/hypoxia­inducible factor­1α pathway in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and accounts for ~6% of all types of human cancer worldwide, particularly in Asia. The incidence and mortality rates in the USA have also rapidly increased. Saikosaponin­d (SSD), a saponin derivative extracted from several species of Bupleurum (Umbelliferae), possesses unique biological activities, including anti­inflammatory, antihepatitic and immunomodulatory effects. Our previous studies have demonstrated that SSD inhibits the proliferation and induces the apoptosis of HCC SMMC­7721 cells by downregulating the expression of cyclooxygenase (COX)­2 and decreasing the production of prostaglandin E2. However, the specific mechanism underlying how SSD controls the expression of COX­2 remains to be elucidated. In the present study, it was demonstrated that hypoxia inducible factor­1α (HIF­1α) was responsible for the expression of COX­2 under hypoxic conditions in HCC cells, and the activation of signal transducer and activator of transcription 3 (STAT3) was required for the expression of HIF­1α. SSD treatment inhibited STAT3 activation [phosphorylation of STAT3 (p­STAT3)], reduced the protein level of HIF­1α and decreased the expression of COX­2. These results suggested that SSD may target HCC cells by suppressing the expression of COX­2 through the p­STAT3/HIF­1α pathway.