Ischemic stroke (IS) is a leading cause of death and long-term disability worldwide. The Naoshuantong capsule (NC), a traditional Chinese patent medicine, has been extensively used in the treatment of stroke in China. However, the clinical efficacy and safety of NC have not been finally verified through rigorous randomized controlled trials. Therefore, this randomized, multicenter, double-blinded, placebo-controlled trial is designed to investigate the efficacy and safety of NC in high-recurrence-risk patients with acute IS within 72 h after symptom onset. An estimated 3150 participants at age of 18 to 80 years with Essen stroke risk score ≥ 3 and National Institutes of Health Stroke Scale score ≤ 15 from approximately 100 Chinese hospitals will be randomly assigned in a 1:1 ratio to the NC group (NC 3 capsules 3 times daily for 90 days) or control group (NC placebo 3 capsules 3 times daily for 90 days). Guideline-based standard medical care will be used in both groups. The primary efficacy outcome is any stroke (ischemic or hemorrhagic) within 90 days after symptom onset. The primary safety outcome is severe adverse events within 90 days. To our knowledge, this study is the first double-blind trial to assess the efficacy and safety of NC in patients with acute IS. Findings of the trial will be valuable in improving evidence regarding the clinical application of NC therapy in patients with mild- to moderate-stroke at high risk of recurrence.
Clinical trial registration: The Chinese Clinical Trial Registry (ChiCTR), identifier ChiCTR2300075877.
To investigate the association between circulating histidine levels and the risk of atrial fibrillation (AF) onset and recurrence, and to explore potential underlying mechanisms. We analyzed data from 221,277 AF-free participants in the UK Biobank and from 44 patients with paroxysmal or persistent AF undergoing catheter ablation, in whom histidine was measured in both peripheral and intracardiac blood. Associations with incident and recurrent AF were evaluated using Cox proportional hazards models, subgroup analyses, and sensitivity analyses. Receiver operating characteristic analysis assessed the predictive value of histidine for AF recurrence. Mechanistic studies included a sheep AF model to examine the impact of electrical remodeling on atrial histidine metabolism, and neonatal rat cardiomyocyte experiments to assess histidine’s effects on cell viability and gene expression. Over a median follow-up of 13.6 years, 14,427 participants developed new-onset AF. Higher histidine levels were associated with a lower risk of AF (hazard ratio per standard deviation: 0.95; 95% confidence interval: 0.94–0.97), with consistent findings across sensitivity analyses. In the ablation cohort, histidine predicted AF recurrence with 76% sensitivity and 77% specificity (area under the receiver operating characteristic curve = 0.75; 95% confidence interval: 0.59–0.90). In the sheep AF model, histidine levels remained stable despite increased 3-methylhistidine, indicating no effect of electrical remodeling on histidine metabolism. Histidine demonstrated a dose-dependent effect on cardiomyocyte viability, enhancing activity at nanomolar concentrations while reducing it at micromolar levels. The downregulation of oxidative phosphorylation (OXPHOS) genes at higher histidine doses, together with the reduction in relative MitoSOX intensity, suggests a dose-dependent modulation of mitochondrial function, potentially balancing energy production and oxidative stress. Histidine is inversely associated with AF risk and may serve as a predictive biomarker for AF recurrence. Experimental findings suggest that changes in histidine may precede AF development, supporting its potential as a modifiable metabolic target.
Adherence to high cardiovascular health (CVH) is effective for preventing atherosclerotic cardiovascular disease, its impact on degenerative valvular heart disease (VHD) remains poorly understood. We aimed to investigate the associations of CVH status, reflected by Life’s Essential 8 (LE8), with incident VHD, and the potential modification of genetic susceptibility. A total of 262,864 participants without VHD at baseline were included from the UK Biobank. CVH status was categorized into 3 groups according to LE8 scores: low (0–49), moderate (50–79), and high (80–100). Genetic susceptibility to aortic valve stenosis (AS) was assessed using a polygenic risk score (PRS) and categorized into tertiles. Fine–Gray competing risk models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multiplicative and additive interactions between CVH and PRS were evaluated. The mean (SD) age was 56.0 (8.1) years, and 51.1% of participants were female. During a mean follow-up of 13.4 years, 6371 incident VHD cases were recorded, including 2754 AS, 1013 aortic valve regurgitation, and 3089 mitral valve regurgitation. Compared with individuals with low LE8 scores, the multivariable-adjusted HRs of incident VHD risk for those with moderate and high LE8 scores were 0.82 (95% CI: 0.74–0.90) and 0.79 (95% CI: 0.70–0.90), respectively. Notably, optimal CVH status was significantly associated with a reduced risk of incident AS, but not with mitral valve regurgitation or aortic valve regurgitation. Compared with low CVH status, AS risk was decreased by 33% and 50% in the moderate (HR: 0.67, 95% CI: 0.59–0.77) and high CVH groups (HR: 0.50, 95% CI: 0.41–0.61), respectively. The PRS of AS did not modify these associations. Nonetheless, adults with both low CVH status and high genetic susceptibility had the highest risk of AS, with a nearly 4-fold increase compared with those with high CVH condition and low genetic predisposition. Both lifestyle behaviors and biological features of CVH were significantly associated with AS incidence. Among the individual LE8 components, body mass index, sleep duration, and nicotine exposure had the strongest effects on valvular outcomes. Higher LE8 scores were significantly associated with a lower incidence of AS, irrespective of genetic susceptibility. These findings indicate that optimal CVH is associated with a lower risk of AS across genetic backgrounds.