Effects of levothyroxine in subclinical hypothyroidism and heart failure with reduced ejection fraction: An open-label randomized trial.

We report a randomized, multicenter, open-label trial (ClinicalTrials.gov: NCT03096613) to investigate the clinical benefits of levothyroxine (L-T4) administration in subclinical hypothyroidism (SCH) patients with heart failure with reduced ejection fraction (HFrEF). Overall, 117 patients were enrolled and received L-T4 plus standard HFrEF treatment (experimental group, N = 57) or standard HFrEF therapy alone (control group, N = 60). The change of 6-min walk test distance in the experimental group was significantly higher than that in the control group at 24 weeks (70.08 ± 85.76 m vs. 27.73 ± 82.00 m, mean difference [95% confidence interval (CI)] 46.90 [12.90, 80.90], p < 0.001). Improvements in New York Heart Association (NYHA) classification (p = 0.033) and thyroid function were significant. Adverse event incidence was similar between groups (risk ratio [95% CI]: 0.942 1.053 (0.424, 2.616); p = 0.628). L-T4 addition to HFrEF treatment improved activity tolerance, NYHA class, and thyroid function within 6 months, suggesting its potential for combined therapy in HFrEF patients with SCH. Future double-blind, placebo-controlled trials should be performed to confirm these results.

Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure.

BACKGROUND: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF. METHODS: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on ß-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF. RESULTS: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the ß-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF. CONCLUSIONS: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.

Safety and efficacy of the DragonFly system for transcatheter valve repair of degenerative mitral regurgitation: one-year results of the DRAGONFLY-DMR trial.

BACKGROUND: Severe degenerative mitral regurgitation (DMR) can cause a poor prognosis if left untreated. For patients considered at prohibitive surgical risk, transcatheter edge-to-edge repair (TEER) has become an accepted alternative therapy. The DragonFly transcatheter valve repair system is an innovative evolution of the mitral TEER device family to treat DMR. AIMS: Herein we report on the DRAGONFLY-DMR trial (ClinicalTrials.gov: NCT04734756), which was a prospective, single-arm, multicentre study on the safety and effectiveness of the DragonFly system. METHODS: A total of 120 eligible patients with prohibitive surgical risk and DMR ≥3+ were screened by a central eligibility committee for enrolment. The study utilised an independent echocardiography core laboratory and clinical event committee. The primary endpoint was the clinical success rate, which measured freedom from all-cause mortality, mitral valve reintervention, and mitral regurgitation (MR) >2+ at 1-year follow-up. RESULTS: At 1 year, the trial successfully achieved its prespecified primary efficacy endpoint, with a clinical success rate of 87.5% (95% confidence interval: 80.1-92.3%). The rates of major adverse events, all-cause mortality, mitral valve reintervention, and heart failure hospitalisation were 9.0%, 5.0%, 0.8%, and 3.4%, respectively. MR ≤2+ was 90.4% at 1 month and 92.0% at 1 year. Over time, left ventricular reverse remodelling was observed (p<0.05), along with significant improvements in the patients' functional and quality-of-life outcomes, shown by an increase in the New York Heart Association Class I/II from 32.4% at baseline to 93.6% at 12 months (p<0.001) and increased Kansas City Cardiomyopathy Questionnaire (KCCQ) score of 31.1±18.2 from baseline to 12 months (p<0.001). CONCLUSIONS: The DRAGONFLY-DMR trial contributes to increasing evidence supporting the safety and efficacy of TEER therapy, specifically the DragonFly system, for treating patients with chronic symptomatic DMR 3+ to 4+ at prohibitive surgical risk.

Metformin alleviates bevacizumab-induced vascular endothelial injury in mice through growth differentiation factor 15 upregulation.

Objectives: Bevacizumab is a commonly used anticancer drug in clinical practice, but it often leads to adverse reactions such as vascular endothelial damage, hypertension, arterial and venous thrombosis, and bleeding. This study investigated the protective effects of metformin against bevacizumab-induced vascular injury in a mouse model and examined the possible involvement of GDF15/PI3K/AKT/FOXO/PPARγ signaling in the effects. Materials and Methods: C57 male mice were purchased. To investigate metformin, the mice were assigned to the saline, bevacizumab (15 mg every 3 days), metformin (1200 mg/day), and bevacizumab+metformin groups. To investigate GDF15, the mice were assigned to the siNC+bevacizumab, siNC+bevacizumab+metformin, siGDF15+bevacizumab, and siGDF15+bevacizumab+metformin groups. Histological staining was used to evaluate vascular injury. Flow cytometry was used to evaluate apoptosis. ELISA was used to measure plasma endothelial injury markers and proinflammatory cytokines. qRT-PCR and western blot were used to determine the expression of GDF15 and PI3K/AKT/FOXO/PPARγ in aortic tissues. Results: Metformin alleviated bevacizumab-induced abdominal aortic injury, endothelial cell apoptosis, and systemic inflammation in mice (all P<0.05). Metformin up-regulated GDF15 expression and PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05). siGDF15 abolished the vascular protective and anti-inflammatory effects of metformin (all P<0.05). siGDF15 suppressed PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05). Conclusion: Metformin attenuates bevacizumab-induced vascular endothelial injury, apoptosis, and systemic inflammation by activating GDF15/PI3K/AKT/FOXO/PPARγ signaling.

Circulating biomarker- and magnetic resonance-based nomogram predicting long-term outcomes in dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) has a high mortality rate and is the most common indication for heart transplantation. Our study sought to develop a multiparametric nomogram to assess individualized all-cause mortality or heart transplantation (ACM/HTx) risk in DCM patients. METHODS: The present study is a retrospective cohort study. The demographic, clinical, blood test, and cardiac magnetic resonance imaging (CMRI) data of DCM patients in the tertiary center (Fuwai Hospital) were collected. The primary endpoint was ACM/HTx. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for variable selection. Multivariable Cox regression was used to develop a nomogram. The concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. RESULTS: A total of 218 patients were included in the present study. They were randomly divided into a training cohort and a validation cohort. The nomogram was established based on eight variables, including mid-wall late gadolinium enhancement, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-diastolic volume index, free triiodothyronine, and N-terminal pro-B type natriuretic peptide. The AUCs regarding 1-year, 3-year, and 5-year ACM/HTx events were 0.859, 0.831, and 0.840 in the training cohort and 0.770, 0.789, and 0.819 in the validation cohort, respectively. The calibration curve and DCA showed good accuracy and clinical utility of the nomogram. CONCLUSIONS: We established and validated a circulating biomarker- and CMRI-based nomogram that could provide a personalized prediction of ACM/HTx for DCM patients, which might help risk stratification and decision-making in clinical practice.

Observational and genetic associations of adiposity with cardiopulmonary multimorbidity: Linear and nonlinear Mendelian randomization analysis.

OBJECTIVE: Whether adiposity traits are causal risk factors for cardiopulmonary multimorbidity (CP-MM) remains largely unknown. The aim of this study was to examine the causal role of adiposity traits in the development of CP-MM. METHODS: This study involved 408,886 participants from the UK Biobank who had complete phenotypic and genetic data. Cox regression and Mendelian randomization (MR) analyses were conducted separately for observational and causal associations. RESULTS: During a median follow-up of 8.7 years, 1492 incident CP-MM were ascertained. In observational analysis, individuals with obesity had a hazard ratio (HR) of 1.51 (95% confidence intervals [CI]: 1.30-1.75) for developing CP-MM, compared with those with normal body mass index (BMI). Restricted cubic spline analyses showed a U-shaped relationship between continuous BMI and CP-MM (p < 0.001), whereas WHRadjBMI exhibited a linear relationship (p = 0.828). Joint analysis revealed that maintaining ideal waist-hip ratio (WHR) in adults with overweight is still effective in preventing CP-MM. In linear MR analysis, 1 kg/m2 increase in genetically predicted BMI and per 1% higher in genetically predicted WHRadjBMI was associated with 9% and 10% higher risk for incident CP-MM, respectively. Nonlinear MR analyses demonstrated linearity between genetically predicted BMI or WHRadjBMI and CP-MM. CONCLUSIONS: Adiposity may play a causal role in CP-MM development and represent a promising approach for multimorbidity prevention.

LncRNADisease v3.0: an updated database of long non-coding RNA-associated diseases.

Systematic integration of lncRNA-disease associations is of great importance for further understanding their underlying molecular mechanisms and exploring lncRNA-based biomarkers and therapeutics. The database of long non-coding RNA-associated diseases (LncRNADisease) is designed for the above purpose. Here, an updated version (LncRNADisease v3.0) has curated comprehensive lncRNA (including circRNA) and disease associations from the burgeoning literatures. LncRNADisease v3.0 exhibits an over 2-fold increase in experimentally supported associations, with a total of 25440 entries, compared to the last version. Besides, each lncRNA-disease pair is assigned a confidence score based on experimental evidence. Moreover, all associations between lncRNAs/circRNAs and diseases are classified into general associations and causal associations, representing whether lncRNAs or circRNAs can directly lead to the development or progression of corresponding diseases, with 15721 and 9719 entries, respectively. In a case study, we used the data of LncRNADisease v3.0 to calculate the phenotypic similarity between human and mouse lncRNAs. This database will continue to serve as a valuable resource for potential clinical applications related to lncRNAs and circRNAs. LncRNADisease v3.0 is freely available at http://www.rnanut.net/lncrnadisease.

Diagnostic accuracy of noninvasive fractional flow reserve derived from computed tomography angiography in ischemia-specific coronary artery stenosis and indeterminate lesions: results from a multicenter study in China.

Background: To determine the diagnostic performance of a novel computational fluid dynamics (CFD)-based algorithm for in situ CT-FFR in patients with ischemia-induced coronary artery stenosis. Additionally, we investigated whether the diagnostic accuracy of CT-FFR differs significantly across the spectrum of disease and analyzed the influencing factors that contribute to misdiagnosis. Methods: Coronary computed tomography angiography (CCTA), invasive coronary angiography (ICA), and FFR were performed on 324 vessels from 301 patients from six clinical medical centers. Local investigators used CCTA and ICA to conduct assessments of stenosis, and CT-FFR calculations were performed in the core laboratory. For CCTA and ICA, CT-FFR ≤ 0.8 and a stenosis diameter ≥ 50% were identified as lesion-specific ischemia. Univariate logistic regression models were used to assess the effect of features on discordant lesions (false negative and false positive) in different CT-FFR categories. The diagnostic performance of CT-FFR was analyzed using an invasive FFR ≤ 0.8 as the gold standard. Results: The Youden index indicated an optimal threshold of 0.80 for CT-FFR to identify functionally ischemic lesions. On a per-patient basis, the diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for CT-FFR were 96% (91%-98%), 92% (87%-96%), 94% (90%-96%), 91% (85%-95%), and 96% (92%-99%), respectively. The diagnostic efficacy of CT-FFR was higher than that of CCTA without the influence of calcification. Closer to the cut point, there was less certainty, with the agreement between the invasive FFR and the CT-FFR being at its lowest in the CT-FFR range of 0.7-0.8. In all lesions, luminal stenosis ≥ 50% significantly affected the risk of reduced false negatives (FN) and false positives (FP) results by CT-FFR, irrespective of the association with calcified plaque. Conclusions: In summary, CT-FFR based on the new parameter-optimized CFD model has a better diagnostic performance than CTA for lesion-specific ischemia. The presence of calcified plaque has no significant effect on the diagnostic performance of CT-FFR and is independent of the degree of calcification. Given the range of applicability of our software, its use at a CT-FFR of 0.7-0.8 requires caution and must be considered in the context of multiple factors.

Prognostic implication of liver fibrosis scores in patients with non-ischemic dilated cardiomyopathy.

Aims: Liver fibrosis was associated with adverse outcomes in various cardiovascular diseases. The current risk stratification of non-ischemic dilated cardiomyopathy (NIDCM) still largely depends on the left ventricular ejection fraction (LVEF). At present, the relationship between liver fibrosis and prognosis in patients with NIDCM remains blank. Methods and results: A total of 433 NIDCM patients were analysed in this study. Liver fibrosis was assessed by three liver fibrosis scores (LFS), including aspartate aminotransferase to platelet ratio index (APRI), aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT ratio), and gamma-glutamyltransferase to platelet ratio (GPR). The primary endpoint was defined as all-cause mortality or heart transplantation (ACM/HTx). During a median follow-up period of 1.7 years, 140 ACM/HTx events occurred. Positive associations were observed between LFS and ACM/HTx. Patients with elevated APRI, AST/ALT ratio, and GPR scores exhibited increased ACM/HTx (all P < 0.05). Intermediate-to-high APRI [hazard ratio (HR) 1.66, 95%CI 1.06-2.61, P = 0.027], AST/ALT ratio (HR 1.59, 95%CI 1.07-2.36, P = 0.021), and GPR (HR 1.64, 95%CI 1.11-2.42, P = 0.013) were independently associated with increased risk of ACM/HTx, even after adjusting for LVEF and other covariates. The positive relationship remains consistent across different subgroups, including those with diabetes and obesity. Conclusions: Elevated liver fibrosis scores were associated with a worse outcome beyond LVEF in patients with NIDCM, which may provide additional prognostic value in the management of NIDCM.

High triglyceride-glucose (TyG) index is associated with poor prognosis of heart failure with preserved ejection fraction.

BACKGROUND: The impact of insulin resistance on the prognosis of heart failure with preserved ejection fraction (HFpEF) remains unknown. This study aimed to investigate the association between the triglyceride-glucose (TyG) index, an easily calculated marker of insulin resistance, and the long-term prognosis of HFpEF. METHODS: A total of 823 patients with HFpEF were enrolled in the study. The TyG index was determined using the formula ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). The primary endpoint was all-cause death. The secondary endpoints were cardiovascular (CV) death and heart failure (HF) rehospitalization. Restricted cubic spline, multivariate Cox proportional hazard models, and competing risk models were used for analyses. RESULTS: During a median follow-up period of 3.16 years, 147 (17.8%) all-cause deaths, 139 (16.8%) CV deaths, and 222 (27.0%) HF rehospitalizations occurred. Restricted cubic spline analysis revealed a J-shaped association between the TyG index and the mortality and rehospitalization rates. In the multivariate Cox proportional hazard models, compared with those in the lowest TyG index tertile, patients in the highest tertile exhibited the greatest susceptibility to all-cause death (HR 1.53, 95% CI 1.19-1.98) and CV death (HR 1.52, 95% CI 1.19-1.96). In the competing risk model, a significant association between the TyG index and HF rehospitalization was observed (HR 1.31, 95% CI, 1.07-1.61). CONCLUSION: A high TyG index is associated with an increased risk of mortality and rehospitalization in patients with HFpEF. The TyG index may serve as a promising prognostic marker for patients with HFpEF.

Association of dietary inflammatory index with helicobacter pylori infection and mortality among US population.

BACKGROUND: Limited research has been conducted on the potential relationship between the dietary inflammation index (DII) and mortality, particularly in individuals with Helicobacter pylori (H. pylori) infection. This study aimed to investigate the association between the DII and H. pylori infection, as well as their respective impacts on all-cause mortality in a cohort of individuals with or without H. pylori infection. METHODS: Data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) were utilized for this study, with a final of 4370 participants included. Both univariable and multivariable-adjusted logistic regression analyses were employed to explore the relationship between H. pylori infection and pertinent covariates. Cox regression analysis, as well as restricted regression cubic spline analysis, were utilized to assess the association between DII and all-cause mortality among individuals with or without H. pylori infection. RESULTS: The findings demonstrated a positive correlation between DII scores and H. pylori infection, even after adjusting for potential confounding factors. Moreover, higher DII scores were significantly associated with an elevated risk of mortality exclusively in individuals with H. pylori infection, while no such association was observed in the uninfected population. Additional analysis using restricted cubic spline modeling revealed a positive linear relationship between DII scores as a continuous variable and the adjusted risk of all-cause mortality specifically in H. pylori-infected patients. CONCLUSION: The results of this study indicated that DII was positively correlated with an increased risk of H. pylori infection and was associated with a heightened risk of all-cause mortality solely in individuals with H. pylori infection. Consequently, DII might serve as a useful tool for risk stratification in the H. pylori-infected population among U.S. adults. Further research is warranted to elucidate the underlying mechanisms and potential clinical implications of these findings.

Diagnostic performance of a novel automated CT-derived FFR technology in detecting hemodynamically significant coronary artery stenoses: A multicenter trial in China.

BACKGROUND AND AIMS: Computed tomography-derived fractional flow reserve (CT-derived FFR) algorithms have emerged as promising noninvasive methods for identifying hemodynamically significant coronary artery disease (CAD). However, its broad adaption is limited by the complex workflow, slow processing, and supercomputer requirement. Therefore, CT-derived FFR solutions capable of producing fast and accurate results could help deliver time-sensitive results rapidly and potentially alter patient management. The current study aimed to determine the diagnostic performance of a novel CT-derived FFR algorithm, esFFR, on patients with CAD was evaluated. METHODS: 329 patients from 6 medical centers in China were included in this prospective study. CT-derived FFR calculations were performed on 350 vessels using the esFFR algorithm using patients' presenting coronary computed tomography angiography (CCTA) images, and results and processing speed were recorded. Using invasive FFR measurements from direct coronary angiography as the reference standard, the diagnostic performance of esFFR and CCTA in detecting hemodynamically significant lesions were compared. Post-hoc analyses were performed for patients with calcified lesions or stenoses within the CT-derived FFR diagnostic "gray zone." RESULTS: The esFFR values correlated well with invasive FFR. The sensitivity, specificity, accuracy, positive and negative predictive value for esFFR were all above 90%. The overall performance of esFFR was superior to CCTA. Coronary calcification had minimal effects on esFFR's diagnostic performance. It also maintained 85% of diagnostic accuracy for "gray zone" lesions, which historically was <50%. The average esFFR processing speed was 4.6 ± 1.3 minutes. CONCLUSIONS: The current study demonstrated esFFR had high diagnostic efficacy and fast processing speed in identifying hemodynamically significant CAD.

Changes in Drug Clinical Trials of Thyroid Diseases in China, 2009-2022.

Objective: The incidence rate of thyroid diseases increased worldwide. This study aims to overview the changing landscape of drug clinical trials on thyroid disease during 2009-2022. Methods: The detailed information of thyroid disease drug trials registered on the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform for Drug Clinical Studies was searched and collected. The thyroid drug clinical trials were analyzed by the characteristics, time trends, indications, and geographical distribution. Results: Sixty-five thyroid disease drug clinical trials were launched from 2009 to 2022 in China, which included 21 trials in nontumorous thyroid disease and 44 trials in thyroid carcinoma. The number of registered trials of thyroid diseases including thyroid carcinoma and nontumorous thyroid disease increased steadily from 2009 to 2020. Bioequivalence studies accounted for the largest proportion (32[49.2%]), while phase I and Phase II studies both only accounted for 18.5% (12/65). A significant difference was observed in the trials phase, and randomization between thyroid carcinoma and nontumorous thyroid disease. In terms of clinical indications and drug mechanisms, the number of trials in multi-target tyrosine kinase inhibitors for thyroid carcinoma (n=35) ranked first, followed by thyroid hormone for hypothyroidism (n=7), thyrotropin for thyroid carcinoma (n=6). Sixty-five trials were led by 36 principal investigator (PI) units, and more than 30% of PI-leading units were located in Shanghai (n=7) and Beijing (n=4). Conclusion: During the past 13 years, the development of thyroid diseases drugs trials has achieved certain progress in thyroid carcinoma, especially the molecular targeted therapy, yet the development of drug trials on nontumorous thyroid disease was very slow.

Level of evidence supporting the Chinese cardiovascular disease clinical practice guidelines and its evolution in the past two decades.

Background: Clinical practice is guided by guidelines in the era of evidence-based medicine to improve healthcare. The consistency between the strength of recommendations and the underlying quality of evidence in clinical guidelines and its evolution dynamically reflects the status of medical practice in important aspects. This study aimed to evaluate the levels of evidence (LOEs) supporting different classes of recommendations (CORs) in Chinese cardiovascular disease (CVD) guidelines between 2003 and 2021, and changes over time. Methods: Clinical guideline documents on cardiovascular topics issued by leading professional organizations were retrieved in the Databases of SinoMed and Wanfang Med Online from inception to June 2021. All guidelines were screened through abstract and full-text reading, and included if satisfying the pre-specified criteria. 79 Chinese guideline documents on 12 sub-topics including a total of 5195 recommendations and the designated CORs/LOEs, were abstracted. The number of recommendations of Class Ⅰ, Class Ⅱ, Class Ⅲ, LOE A, LOE B, and LOE C were identified for each guideline document. The proportion of CORs, LOEs, and COR-LOE combinations in guidelines and the changes among those with ≥2 versions. Findings: A total of 79 guidelines were included in the analysis. When examining the status of current guidelines, among the 3325 recommendations derived from 59 documents during 2011-2021, 735 recommendations (22.1%) were classified as LOE A, 1280 (38.5%) as LOE B, and 1310 (39.4%) as LOE C. 596 recommendations (17.9%) were characterized as Class Ⅰ-LOE A, accounting for the majority of LOE A recommendations but only one-third of Class I recommendations. Evidence levels varied greatly across different sub-topics and individual guidelines. There are 9 guidelines on 5 sub-topics having ≥2 versions. When analyzing the changes over time, although an increase was observed in the total number of recommendations, the proportion of recommendations designated as Class Ⅰ-LOE A did not significantly improve (19.1% [current] vs 19.0% [prior], p = 0.97). Interpretation: In current Chinese CVD guidelines, the high level of evidence lacks, and its alignment with strong recommendations is deficient. Although it shows moderate improvements in certain major topics (e.g., coronary artery disease, interventional therapy, surgery) in the past two decades, the overall proportion of Class I-LOE A recommendations remains small, suggesting that conduction, and particularly translation, of high-quality studies like RCTs addressing CVDs-related questions are still essential and demanded, especially for areas with less attention. Funding: This study was supported by Beijing Nova Program from Beijing Municipal Science & Technology Commission (Z211100002121063, Z201100006820002); Fundamental Research Funds for the Central Universities (3332022023); National Key R&D Program of China (2020YFC2004705); CAMS Innovation Fund for Medical Sciences (2021-I2M-5-003); National Natural Science Foundation of China (81825003, 91957123, 82270376).

In vivo self-assembled shape-memory polyurethane for minimally invasive delivery and therapy.

Advanced elastomers are highly in demand for the fabrication of medical devices for minimally invasive surgery (MIS). Herein, a shape memory and self-healing polyurethane (PCLUSe) composed of semi-crystalline poly(ε-caprolactone) (PCL) segments and interchangeable and antioxidative diselenide bonds was designed and synthesized. The excellent shape memory of PCLUSe contributed to the smooth MIS operation, leading to less surgical wounds than in the case of sternotomy. The diselenide bonds of PCLUSe contributed to the rapid self-healing under 405 nm irradiation within 60 s, and the alleviation of tissue oxidation post injury. After being delivered through a 10 mm diameter trocar onto a beating canine heart by MIS, two shape-recovered PCLUSe films self-assembled (self-healing) into a larger single patch (20 × 10 × 0.2 mm3) under the trigger of laser irradiation in situ, which could efficiently overcome the limited-size problem within MIS and meet a larger treatment area. The diselenide bonds in the PCLUSe cardiac patches protected the myocardium under oxidative stress post myocardial infarction (MI), and significantly maintained the cardiac functions.

The impact of the stress hyperglycemia ratio on mortality and rehospitalization rate in patients with acute decompensated heart failure and diabetes.

BACKGROUND: The relationship between stress hyperglycemia and long-term prognosis in acute decompensated heart failure (ADHF) patients is unknown. This study investigated the associations of stress hyperglycemia with mortality and rehospitalization rates among ADHF patients with diabetes. METHODS: We consecutively enrolled 1904 ADHF patients. Among them, 780 were with diabetes. Stress hyperglycemia was estimated using the stress hyperglycemia ratio (SHR), which was calculated by the following formula: SHR = admission blood glucose/[(28.7 × HbA1c%) - 46.7]. All diabetic ADHF subjects were divided into quintiles according to the SHR. The primary endpoint was all-cause death at the 3-year follow-up. The secondary endpoints were cardiovascular (CV) death and heart failure (HF) rehospitalization at the 3-year follow-up. A Cox proportional hazards model and restricted cubic spline analysis were used to elucidate the relationship between the SHR and the endpoints in diabetic ADHF patients. Further analyses were performed to examine the relationships between SHR and the outcomes in heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). RESULTS: A total of 169 all-cause deaths were recorded during a median follow-up of 3.24 years. Restricted cubic spline analysis suggested a U-shaped association between the SHR and the mortality and rehospitalization rates. Kaplan-Meier survival analysis showed the lowest mortality in the 2nd quintile (P = 0.0028). Patients categorized in the highest range (5th quintile) of SHR, compared to those in the 2nd quintile, exhibited the greatest susceptibility to all-cause death (with a hazard ratio [HR] of 2.76 and a 95% confidence interval [CI] of 1.63-4.68), CV death (HR 2.81 [95% CI 1.66-4.75]) and the highest rate of HF rehospitalization (HR 1.54 [95% CI 1.03-2.32]). Similarly, patients in the lowest range (1st quintile) of SHR also exhibited significantly increased risks of all-cause death (HR 2.33, 95% CI 1.35-4.02) and CV death (HR 2.32, 95% CI 1.35-4.00). Further analyses indicated that the U-shape association between the SHR and mortality remained significant in both HFpEF and HFrEF patients. CONCLUSION: Both elevated and reduced SHRs indicate an unfavorable long-term prognosis in patients with ADHF and diabetes.

The first clinical data of the SAPIEN 3 aortic valve in the treatment of aortic stenosis in China.

Background: Data on outcomes following transcatheter aortic valve replacement with SAPIEN 3 in China is limited as it was approved by the National Medical Products since 2020. The present study was designed to collect clinical data on the SAPIEN 3 aortic valve in Chinese patients with bicuspid aortic valve and tricuspid aortic valve stenosis. Methods: We analyzed the patient characteristics, procedural features and procedural outcomes of the first 438 patients (223 for bicuspid aortic valve and 215 tricuspid aortic valve) from 21 provinces in 74 sites treated with the SAPIEN 3 valve system for transcatheter aortic valve replacement between September 2020 and May 2022. Results: Procedural mortality was 0.7%. 5 cases during the operation were converted to surgery. Among 438 cases, permanent pacemaker implantation was performed in a total of 12 cases (2.7%). The patient had severe leaflet calcification of the aortic valve, with moderate and severe calcification reaching 39.7% and 35.2% respectively. The size of the implanted valves was predominantly 26 mm and 23 mm, reaching 42.5% and 39.5% respectively. The incidence of moderate or severe perivalvular leak in the postoperative period was 0.5%, with a predominance of 90/10 and 80/20 valve deployment height. There was a significant difference in the deployment height of the valve between bicuspid aortic valve and tricuspid aortic valve, with the bicuspid aortic valve having a more deployment height of 90/10. Annulus size in bicuspid aortic valve group was significantly larger than tricuspid aortic valve group. Valve sizing for oversized, within size, and undersized were different between bicuspid aortic valve and tricuspid aortic valve. Conclusions: Procedural success rates were high, with similar and good results for bicuspid aortic valve and tricuspid aortic valve, low perivalvular leak for both valve types, and low permanent pacemaker implantation rates for both valve types. Annulus size, valve sizing and coronary artery height were significantly different in the BAV and TAV group.

The triglyceride-glucose index as a potential protective factor for hypertrophic obstructive cardiomyopathy without diabetes: evidence from a two-center study.

OBJECTIVE: This study aimed to investigate the relationship between the TyG (Triglyceride-glucose index) and the prognosis of patients with HOCM (hypertrophic obstructive cardiomyopathy) without diabetes. RESEARCH DESIGN AND METHODS: A total of 713 eligible patients with HOCM were enrolled in this study and divided into two groups based on treatment: an invasive treatment group (n = 461) and a non-invasive treatment group (n = 252). The patients in both two groups were then divided into three groups based on their TyG index levels. The primary endpoints of this study were Cardiogenic death during long-term follow-up. Kaplan-Meier analysis was used to study the cumulative survival of different groups. Restricted cubic spline was used to model nonlinear relationships between the TyG index and primary endpoints. Myocardial perfusion imaging/Myocardial metabolic imaging examinations were performed to assess glucose metabolism in the ventricular septum of the HOCM patients. RESULTS: The follow-up time of this study was 41.47 ± 17.63 months. The results showed that patients with higher TyG index levels had better clinical outcomes (HR, 0.215; 95% CI 0.051,0.902; P = 0.036, invasive treatment group; HR, 0.179; 95% CI 0.063,0.508; P = 0.001, non-invasive treatment group). Further analysis showed that glucose metabolism in the ventricular septum was enhanced in HOCM patients. CONCLUSIONS: The findings of this study suggest that the TyG index may serve as a potential protective factor for patients with HOCM without diabetes. The enhanced glucose metabolism in the ventricular septum of HOCM patients may provide a potential explanation for the relationship between the TyG index and HOCM prognosis.

Targeting cytokine-like protein FAM3D lowers blood pressure in hypertension.

Current antihypertensive options still incompletely control blood pressure, suggesting the existence of uncovered pathogenic mechanisms. Here, whether cytokine-like protein family with sequence similarity 3, member D (FAM3D) is involved in hypertension etiology is evaluated. A case-control study exhibits that FAM3D is elevated in patients with hypertension, with a positive association with odds of hypertension. FAM3D deficiency significantly ameliorates angiotensin II (AngII)-induced hypertension in mice. Mechanistically, FAM3D directly causes endothelial nitric oxide synthase (eNOS) uncoupling and impairs endothelium-dependent vasorelaxation, whereas 2,4-diamino-6-hydroxypyrimidine to induce eNOS uncoupling abolishes the protective effect of FAM3D deficiency against AngII-induced hypertension. Furthermore, antagonism of formyl peptide receptor 1 (FPR1) and FPR2 or the suppression of oxidative stress blunts FAM3D-induced eNOS uncoupling. Translationally, targeting endothelial FAM3D by adeno-associated virus or intraperitoneal injection of FAM3D-neutralizing antibodies markedly ameliorates AngII- or deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Conclusively, FAM3D causes eNOS uncoupling through FPR1- and FPR2-mediated oxidative stress, thereby exacerbating the development of hypertension. FAM3D may be a potential therapeutic target for hypertension.

The changing landscape of drug clinical trials on cardiometabolic diseases in China, 2009-2021.

BACKGROUND: Cardiometabolic disease is a clinical syndrome characterized by multiple metabolic disorders, with atherosclerosis as the core and cardiovascular and cerebrovascular events as the outcome. Drug research and development (R&D) in cardiometabolic diseases has grown rapidly worldwide. However, the development of cardiometabolic drug clinical trials in China remains unclear. This study aims to depict the changing landscape of drug clinical trials for cardiometabolic diseases in China during 2009-2021. METHODS: The detailed information of drug trials on cardiometabolic diseases registered in the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform was collected between January 1, 2009, and July 1, 2021. The landscape of cardiometabolic drug clinical trials was analyzed by the characteristics, time trends, indications, pharmacological mechanisms, and geographical distribution. RESULTS: A total of 2466 drug clinical trials on cardiometabolic diseases were extracted and analyzed. The annual number of drug trials increased rapidly in the past twelve years. Among all the trials, the bioequivalence trials (1428; 58.3%) accounted for the largest proportion, followed by phase I (555; 22.5%), phase III (278; 11.3%), phase II (169; 6.9%), and phase IV (26; 1.1%). Of 2466 trials, 2133 (86.5%) trials were monomer drugs, only 236 (9.6%) trials were polypills and 97 (3.9%) were traditional Chinese medicine (TCM) compounds. In terms of pharmacological mechanisms, the number of trials in dihydropyridine (DHP) calcium antagonists 321 (11.9%) ranked first, while trials in angiotensin receptor blocker (ARB) 289 (10.7%) and dipeptidyl peptidase-4 (DPP-4) inhibitor 205 (7.6%) ranked second and third place respectively. Of 236 chemical polypills trials, 23 (9.7%) polypills were the combination of DHP calcium antagonists and statins, while others were the combination of two same pharmacological effect agents. As for the geographical distribution of leading units, 36 trials were led by principal investigators (PI) units from Beijing, followed by Jiangsu (n = 29), Shanghai (n = 19), Guangdong (n = 19), and Hunan (n = 19), showing an uneven regional distribution. CONCLUSIONS: Great progress has been made in drug clinical trials on cardiometabolic diseases, especially in antihypertensive agents, hypoglycemic agents, and hypolipidemic agents. However, the insufficient innovation of first-in-class drugs and polypills should be carefully considered by all stakeholders in drug trials.