The ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) is an emerging lipid parameter. An association has been demonstrated with cardiovascular mortality. This study aimed to investigate the link between NHHR and mortality among hypertensive patients.This study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted in the United States from 1999 to 2018. The NHHR was derived from the lipid index. The association between NHHR and mortality in hypertensive patients was evaluated using multivariate Cox regression and Kaplan-Meier survival analysis, with restricted cubic spline curves (RCS) illustrating the nonlinear relationship. Subgroup analyses were conducted to assess the association's stability. The study included 16,259 patients with hypertension. Multivariate Cox regression analyses, adjusted for covariates, indicated that patients in NHHR quartiles Q2 and Q3 exhibited a 14% and 16% reduced risk of all-cause mortality, and a 32% and 33% reduced risk of cardiovascular mortality, respectively, compared to those in Q1. RCS analyses revealed a U-shaped relationship between NHHR and both all-cause and cardiovascular mortality in patients with hypertension. Subgroup analyses further maintained the robustness of this association across most subgroups. In hypertensive patients, NHHR exhibits a U-shaped relationship with both all-cause and cardiovascular mortality. This finding suggests that NHHR may serve as a new predictor of future mortality risk in hypertensive patients, providing a new marker for prognostic prevention in this special population.

Although several studies have demonstrated the relationship between the triglyceride glucose (TyG) index and the prevalence of atrial fibrillation (AF), more attention needs to be paid to patients with AF in intensive care units because the prevalence of AF is as high as one-third of the population. This study investigated the relationship between the TyG index and short-term prognosis in patients with critical care AF. We selected critically ill patients with AF from the MIMIC-IV database and categorized them into quartiles based on their TyG index levels. The primary outcome assessed was 30-day all-cause mortality, with secondary outcomes of 7-day and 15-day all-cause mortality. We utilized Kaplan-Meier survival curves, restricted cubic spline, and Cox proportional hazards regression models to illustrate the relationship between the TyG index and clinical outcomes in critically ill patients with AF. 1,146 critically ill patients with AF were included in this study, with a mean age of 75.90. The female population accounted for 48.43% of the total. Kaplan-Meier survival curves demonstrated a significant association between the TyG index and all-cause mortality at 7, 15, and 30 days. Cox proportional hazards analysis, after adjusting for multiple confounders, revealed a substantial increase in all-cause mortality in the fourth quartile of the TyG index compared to the first quartile (HR = 1.71, 95% CI: 1.17-2.49). Restricted cubic spline further illustrated that higher TyG index were associated with an elevated risk of all-cause mortality in critically ill patients with AF. The stratified analysis provided additional support for the robustness of this association. The TyG index demonstrated a significant association with 7-day, 15-day, and 30-day all-cause mortality in critically ill patients with AF. These findings suggest that the TyG index may serve as a useful tool in identifying AF patients at a higher risk of all-cause mortality, enabling early and effective intervention strategies.

BackgroundGender disparities in mortality have drawn great interest, with previous studies identifying various biological, social, and behavioral factors contributing to the observed gender differences. This study aims to identify the sources of gender disparities in mortality rates and quantify the extent to which these factors mediate the gender differences in all-cause mortality.MethodsData from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2018 were analyzed. A total of 38,924 participants were included in the study. Gender information, socioeconomic status, lifestyle factors, and baseline disease status were obtained through questionnaires. Blood samples were collected to assess serological indicators. All-cause and cardiovascular mortality were considered as primary and secondary outcomes, respectively.ResultsThe study with an average age of 50.1 ± 17.9 years. Among the participants, 50.7% were women, and 41.8% were non-Hispanic White. The median follow-up length was 87 months [Inter-Quartile Range (IQR): 47–128]. Men showed higher rates of all-cause and cardiovascular mortality compared to women in both the general population and the population with cardiovascular disease. After adjustment for potential confounders (age, race, marital status, socioeconomic status, lifestyle level, smoking status, cardiovascular disease, hypertension, diabetes and cancer), the men: women hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.58 [95% Confidence Interval (CI): 1.48–1.68] and 1.60 (95%CI:1.43–1.80) in the general population. Among individuals with cardiovascular disease, the fully adjusted HR for all-cause mortality was 1.34 (95% CI: 1.20 to 1.51), and for cardiovascular mortality, the fully adjusted HRs was 1.52 (95% CI: 1.26 to 1.83). Mediation analysis revealed that uric acid levels significantly mediated the association between gender and all-cause mortality, accounting for 17.53% (95% CI: 11.0% to 23.7%) in the general population and 27.47% (95% CI: 9.0% to 13.6%) in the population with cardiovascular disease.ConclusionsThe study highlights the complex interplay of biological and social factors contributing to gender disparities in mortality. Uric acid was identified as key mediators of the gender-mortality association. These findings can inform targeted interventions aimed at reducing gender disparities in mortality and promoting better public health outcomes.

Introduction Specific lipid-reducing therapeutics, including statins, are known for mitigating cardiovascular diseases due to their comprehensive benefits including anti-inflammatory properties, antioxidative stress response, and enhancement of endothelial function. The objective of our study was to determine the causative impact of lipid-reducing agents (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitor) on the outcomes of pulmonary hypertension via a two-sample Mendelian randomization (MR) analysis. Methods Two types of genetic tools were employed to estimate the exposure to lipid-lowering drugs, comprising expression quantitative trait loci of the drug’s target genes and genetic variations close to or within the target genes related to low-density lipoprotein (LDL cholesterol derived from a genome-wide association study). We utilized summary-data-based MR (SMR) and inverse-variance-weighted MR (IVWMR) methodologies for estimating effect sizes. Results SMR analysis indicated that elevated HMGCR expression correlates with increased pulmonary hypertension risk (β=-0.964, se=0.276). Yet, no evident causative link between HMGCR-regulated LDL cholesterol and COVID-19 hospitalization was observed in the IVW-MR analysis (β = -0.21, se= 0.17). Conclusions Our Mendelian randomization investigation unveiled a possible positive impact of lipid-lowering therapeutics on the prognosis of pulmonary hypertension. Importantly, no causal relation was established between LDL cholesterol and pulmonary hypertension. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Traditional Chinese Medicine Inheritance and Innovation and "Qin Medicine" Development [No. 2021-03-22-001]，Qin Chuangyuan Traditional Chinese Medicine Innovation Research and Development Transformation Project (No.2022-QCYZH-022),the Key Basic Natural Science Foundation of Shaanxi Province [No. 2022JZ-47], the Key Industrial Innovation Chain Project in Shaanxi Province of China [No. 2021ZDLSF02-03 and 2020ZDLSF01-08], the Key Program for the Shaanxi Provincial Health and Health Research Fund Project (No. 2022D024), and the Natural Science Foundation of Shaanxi Province [No. 2019JM-440 and No.2021JQ-911]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The data used in our study is sourced entirely from the Opengwas website, which is a public, ethically-reviewed database. We did not collect data directly from any participants or subjects; thus, our study does not involve direct research or data collection on individuals. The data from the Opengwas website has already undergone appropriate ethical review and approval. Consequently, we believe that our study does not require separate ethical approval in this context. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in our study is sourced entirely from the Opengwas website, which is a public, ethically-reviewed database.

Obesity is a risk factor for heart failure, and patients with obesity and heart failure have a better prognosis. We attempted to explain this paradox by exploring the role of hypertension in obesity and heart failure.We performed univariable and multivariable Mendelian randomization (MR) analyses to investigate causal effects of obesity and hypertension on heart failure. Analysis using the inverse-variance weighted (IVW) method showed that obesity Ⅱ ( OR IVW = 1.10, 95% CI = 1.05–1.15, P = 2.86 × 10 − 5 ) and obesity Ⅰ ( OR IVW = 1.17, 95% CI = 1.11–1.24, P = 8.41 × 10 − 8 ) had a positive effect on the occurrence of heart failure. The IVW method showed a causal effect of obesity Ⅰ ( OR IVW = 1.02, 95% CI = 1.00–1.02, P = 2.807× 10 − 25 ) and obesity Ⅱ ( OR IVW = 1.01, 95% CI = 1.00–1.02, P = 7.14 × 10 − 11 ) on hypertension. After adjusting for hypertension using multivariate IVW, obesity II was not causally associated with heart failure.Both obesity and hypertension are risk factors for heart failure, and the effect of obesity on heart failure is mediated by hypertension.

Evidence of a clear causal relationship between telomere length and aortic aneurysms is limited by the potential for confounding or reverse causation effects. In this study, we used a Mendelian randomisation (MR) approach to investigate this putative causal association.

BackgroundIndex of cardiac electrophysiological balance (iCEB) has been widely used in clinical practice but no studies investigated the association between iCEB and prognosis in the general population.ObjectiveTo assess the correlation between the iCEB and the prognosis in the general population.MethodsThis retrospective cohort study involved adults aged 40–65 years who participated in the Third National Health and Nutrition Examination Survey (NHANES-III) and whose electrocardiograms were in sinus rhythm. The corrected iCEB (iCEBc) was the ratio of corrected QT interval (QTc) to QRS duration, and outcomes were cardiac and all-cause mortality. Cox proportional hazards regression model was used to identify the associations of iCEBc with end point. The value of iCEBc for predicting adverse events was evaluated by reclassification and discrimination analyses.ResultsAmong 5,010 participants (mean age 51.10 ± 7.67 years, 52.5% female), 3,454 (68.9%) were Non-Hispanic White. The mean iCEBc was 4.45 ± 0.56. A total of 2,147 deaths were recorded during a median follow-up of 319 months. The adjusted model shown iCEBc was an independent risk factor for all-cause death. The iCEBc was linearly correlated with all-cause mortality and the optimal cutoff value was 4.57 in males and 4.98 in females. In the resultant model, prolonged iCEBc remained independently associated with a higher rate of mortality (HR: 1.25; 95% CI: 1.11–1.42) and cardiac death (HR: 1.34; 95% CI: 1.04–1.71). Among the complete study population or the group with normal QTc interval, the performance of the predictive model after addition of iCEBc was not weaker than the model after the addition of prolonged QTc.ConclusionElevated iCEBc (male ≥4.57 and female ≥4.98) is an independent risk factor for cardiac or all-cause death among the middle-age adults. The clinical application value of iCEBc is firmly based on basic physiological principles and its application deserves further attention.

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 β 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.

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.

BackgroundIn 2019, there were 28. 76 million patients with stroke in China, with ~25% of them suffering from cryptogenic stroke (CS). Patent foramen ovale (PFO) is related to CS, and PFO closure can reduce recurrent stroke. To date, no study has investigated the cost-effectiveness of PFO closure vs. medical therapy among such populations in China.MethodsA Markov model with a cycle length of 3 months was established to compare the 30-year cost-effectiveness of PFO closure and medical therapy. The transition probability of recurrent stroke was derived from the RESPECT study, and the costs and utility were obtained from domestic data or studies conducted in China. The primary outcome of this study was the incremental cost-effectiveness ratio (ICER), which represents the incremental cost per quality-adjusted life year (QALY). PFO closure was considered cost-effective if the ICER obtained was lower than the willingness-to-pay (WTP) threshold of 37,654 USD/QALY; otherwise, PFO closure was regarded as not being cost-effective. One-way and probabilistic sensitivity analyses were performed to test the robustness of the results.ResultsAfter a simulation of a 30-year horizon, a cryptogenic stroke patient with PFO was expected to have QALY of 13.15 (15.26 LY) if he received PFO closure and a corresponding value of 11.74 QALY (15.14 LY) after medical therapy. The corresponding costs in both cohorts are US $8,131 and US $4,186, respectively. Thus, an ICER of 2783 USD/QALY and 31264 USD/LY was obtained, which is lower than the WTP threshold. One-way and probabilistic sensitivity analyses showed that the results were robust.ConclusionWith respect to the WTP threshold of three times per capita GDP in China in 2021, PFO closure is a cost-effective method for Chinese cryptogenic stroke patients with PFO, as shown in the 30-year simulation.

BackgroundObservational 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 methodsGenome-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.ResultsIn 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.ConclusionA 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.

Aim: Coronary artery disease (CAD) is a heterogeneous disorder with high morbidity, mortality, and healthcare costs, representing a major burden on public health. Here, we aimed to improve our understanding of the genetic drivers of ferroptosis and necroptosis and the clustering of gene expression in CAD in order to develop novel personalized therapies to slow disease progression. Methods: CAD datasets were obtained from the Gene Expression Omnibus. The identification of ferroptosis- and necroptosis-related differentially expressed genes (DEGs) and the consensus clustering method including the classification algorithm used km and distance used spearman were performed to differentiate individuals with CAD into two clusters (cluster A and cluster B) based expression matrix of DEGs. Next, we identified four subgroup-specific genes of significant difference between cluster A and B and again divided individuals with CAD into gene cluster A and gene cluster B with same methods. Additionally, we compared differences in clinical information between the subtypes separately. Finally, principal component analysis algorithms were constructed to calculate the cluster-specific gene score for each sample for quantification of the two clusters. Results: In total, 25 ferroptosis- and necroptosis-related DEGs were screened. The genes in cluster A were mostly related to the neutrophil pathway, whereas those in cluster B were mostly related to the B-cell receptor signaling pathway. Moreover, the subgroup-specific gene scores and CAD indices were higher in cluster A and gene cluster A than in cluster B and gene cluster B. We also identified and validated two genes showing upregulation between clusters A and B in a validation dataset. Conclusion: High expression of CBS and TLR4 was related to more severe disease in patients with CAD, whereas LONP1 and HSPB1 expression was associated with delayed CAD progression. The identification of genetic subgroups of patients with CAD may improve clinician knowledge of disease pathogenesis and facilitate the development of methods for disease diagnosis, classification, and prognosis.

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.