Wenbo Zhao

Oxidative stress contributes to pulmonary hypertension (PH), but acute redox responses within the pulmonary circulation remain poorly characterized. In this prospective, open-label, single-arm pilot study, 15 patients with PH underwent one 50 min session of remote ischemic conditioning (RIC) during right heart catheterization. Pulmonary arterial (PA) blood was collected immediately before and after RIC. The prespecified primary biomarker family comprised reduced glutathione (GSH) response and the oxidized glutathione-to-GSH (GSSG/GSH) ratio in PA blood-cell and plasma fractions. PA blood-cell GSH response increased (mean paired difference, 118; 95% CI, 83–152; Holm-adjusted p < 0.001), whereas the blood-cell GSSG/GSH ratio decreased (−0.64; 95% CI, −0.81 to −0.46; Holm-adjusted p < 0.001). Plasma glutathione measures were not significant after multiplicity adjustment. PA lactate, the prespecified secondary endpoint, decreased by 0.45 mmol/L (95% CI, 0.20–0.71; p = 0.002). All participants completed RIC without clinically evident acute adverse events. These preliminary findings identify acute PA blood-cell glutathione and metabolic changes associated with RIC; however, the single-arm design precludes causal inference, and confirmation in randomized sham-controlled studies is warranted.

Background and ObjectivesVisit-to-visit blood pressure variability (BPV) may contribute to cerebral white matter lesions (WML) progression, but previous evidence has been inconsistent and limited b...

BACKGROUND: Blood pressure (BP) variability (BPV) is associated with cardiovascular risk beyond mean BP. Whether first-line antihypertensive regimens differentially affect BPV and cardiovascular outcomes remains uncertain. METHODS: We conducted a target trial emulation using pooled individual participant data from 2 randomized trials: ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial). Propensity score matching was used for pairwise comparisons of RAS (renin–angiotensin system) inhibitors, calcium channel blockers (CCBs), and diuretics, as monotherapy or in combination. Follow-up was initiated at a predefined baseline medication assessment. The primary outcome was visit-to-visit systolic BPV, assessed using variation independent of the mean. Secondary outcomes included major adverse cardiovascular events and its individual components. RESULTS: The final cohort included 5779 participants (median of 12 BP measurements and median follow-up of 3.5 years), among whom 2754 were included in the matched analysis. CCB-based regimens were consistently associated with significantly lower systolic BPV compared with both RAS inhibitor-based and diuretic-based regimens. This association was consistent across monotherapy (CCB versus RAS: β=−1.341 [95% CI, −1.930 to −0.752]; P P <0.001). In contrast, RAS inhibitor–based and diuretic-based regimens demonstrated comparable BPV profiles. 215 (3.7%) major adverse cardiovascular event events were observed in the overall cohort. No significant differences in major adverse cardiovascular event or individual components were observed across comparisons. CONCLUSIONS: Among high-risk hypertensive patients receiving target-driven BP management, CCB-based regimens were associated with lower visit-to-visit systolic BPV compared with RAS inhibitor–based and diuretic-based regimens. However, these differences were not accompanied by detectable differences in cardiovascular outcomes.

Background and Aims: Blood pressure variability (BPV) is associated with cardiovascular risk and has been shown to confer prognostic information independent of mean blood pressure (BP). However, the consistency of its incremental predictive value across different clinical settings and populations warrants further investigation. A patient-level pooled analysis of two large randomized trials (SPRINT and ACCORD) was conducted to clarify the association between BPV and major cardiovascular events (MCEs). Methods: Visit-to-visit BPV was calculated from Month 3 onwards using multiple metrics (including variation independent of mean, VIM) in participants with ≥3 visits. Associations between BPV and MCEs (myocardial infarction, stroke, or cardiovascular death) were assessed using Cox regression and restricted cubic splines. Results: Among 18 415 participants (median 12 BP measurements; 3.6-year follow-up), 1244 (6.8%) experienced MCEs. After multivariable adjustment, higher SBP-VIM (highest vs lowest tertile) was associated with a greater risk of MCEs (hazard ratio 1.15, 95% confidence interval 1.00–1.32), with similar associations for myocardial infarction and cardiovascular death. Restricted cubic spline analyses revealed a J-shaped relationship between SBP-VIM and cardiovascular outcomes (all P < .05). The prognostic value of SBP-VIM was comparable to mean SBP. These findings were consistent across alternative BPV metrics and intensified with extended follow-up. Conclusions: Visit-to-visit BPV was independently associated with the risk of MCEs, particularly myocardial infarction and cardiovascular death, with a J-shaped relationship indicating that both low and high BPV may be harmful. This association was independent of mean BP and comparable in prognostic value, underscoring the need to determine optimal BPV targets and explore potential BPV-modulating interventions.

Background: Long‐term outcomes after endovascular treatment (EVT) in acute basilar artery occlusion (BAO) vary substantially, yet metabolic correlates remain incompletely characterized. This study evaluated whether the triglyceride–glucose (TyG) index and TyG–body mass index (TyG‐BMI) are associated with 1‐year functional status and mortality after EVT. Methods: A single‐center registry with prospective data collection was retrospectively analyzed. Consecutive acute BAO patients undergoing EVT within 24 h (December 2012–September 2024) were included. Unfavorable functional outcome at 1 year was defined as modified Rankin Scale (mRS) 4–6; 1‐year all‐cause mortality was also assessed. Multivariable logistic regression was applied, with receiver operating characteristic analyses and prespecified subgroup analyses. Results: The final cohort comprised 298 patients (median age 62 years; 78.5% male), among whom 165 (55.4%) had an unfavorable 1‐year outcome and 109 (36.6%) died. After adjustment, each 1‐SD increase in TyG and TyG‐BMI corresponded to higher odds of unfavorable outcome (TyG OR 1.69, 95% CI 1.25–2.30; TyG‐BMI OR 1.46, 95% CI 1.10–1.96) as well as mortality (TyG OR 1.44, 95% CI 1.09–1.90; TyG‐BMI OR 1.61, 95% CI 1.23–2.12). Discrimination was modest and similar between indices. A significant sex interaction was observed for TyG‐BMI and mortality ( p for interaction = 0.03), with an association in men only. Conclusions: In EVT‐treated acute BAO, TyG and TyG‐BMI may help identify EVT‐treated acute BAO patients at higher risk of poor 1‐year outcome and death. The mortality risk associated with TyG‐BMI was modified by sex, with an effect confined to men.

Background: Previous evidence supports the efficacy and safety of intravenous urokinase thrombolysis in acute ischemic stroke (AIS), with additional advantages in terms of cost-effectiveness. Existing studies suggest that treatment response may be dose-dependent; however, current dosing practices remain largely empirical and lack standardization based on high-quality evidence. Establishing a weight-based dosing regimen is, therefore, essential to maximize therapeutic benefit and minimize risks. Objective: To determine the maximum tolerated dose (MTD) of urokinase and to develop an optimized weight-adjusted dosing protocol for AIS. Methods: OUTSET is a prospective, single-center, phase I, dose-escalation clinical trial using a weight-based, rolling-six design in patients with AIS. Patients who meet the inclusion criteria will be assigned to one of four dose groups (15,000 IU/kg, 20,000 IU/kg, 25,000 IU/kg and 30,000 IU/kg). Urokinase will be administered intravenously, diluted in 100 mL of normal saline, over a period of 30 min. Outcomes: The primary endpoint is the identification of the MTD based on dose-limiting toxicity events, including symptomatic intracranial hemorrhage, major bleeding, and other significant adverse events. Discussion: This study offers a structured, weight-based approach to determining the MTD of intravenous urokinase for AIS using a rolling-six dose-escalation design. By addressing the current lack of standardized, body-weight–adjusted dosing protocols, the findings may enhance the clinical safety and efficacy of urokinase thrombolysis. The results are expected to inform future phase II/III trials and support the development of individualized thrombolytic strategies in routine stroke care. Clinical trial registration: ClinicalTrials.gov identifier: NCT07047326.

Background: In acute ischemic stroke, early neurological deterioration following intravenous thrombolysis (IVT) is common and is associated with unfavorable outcomes, necessitating antiplatelet therapy. TREND‐IVT (Trial of Early Aspirin After Intravenous Thrombolysis for Acute Ischemic Stroke) aims to evaluate the safety and efficacy of 300 mg aspirin administered within 3 hours after the initiation of IVT compared with standard antiplatelet therapy for improving functional outcomes in patients with acute ischemic stroke. Methods: This multicenter, randomized, placebo‐controlled trial in China recruits patients with acute ischemic stroke receiving IVT (alteplase/tenecteplase) who are not scheduled for endovascular therapy. Participants are randomized in a 1:1 ratio to receive either early aspirin or placebo within 3 hours of initiating IVT, followed by guideline‐recommended standard antiplatelet therapy beginning 24 hours after IVT in both groups. The primary outcome is an excellent functional outcome, defined as a modified Rankin Scale (mRS) score 0 to 1 at 90 days. Secondary outcomes will include mRS score 0 to 1 at 30 days, mRS score 0 to 2 at 90 days, ordinal shift analysis of mRS scores at 90 days, and changes in the National Institutes of Health Stroke Scale scores within 7 days. Safety end points will include symptomatic intracerebral hemorrhage, any intracerebral hemorrhage within 48 hours, systemic bleeding, recurrent stroke, other vascular events, mortality, and other adverse events during the 90‐day follow‐up. A sample size of 1184 participants will provide 80% power to detect an 8% intergroup difference in the primary outcome rate (2‐sided α=0.05). Conclusions: The trial will evaluate the safety and efficacy of early antiplatelet therapy with oral aspirin in patients with acute ischemic stroke treated with IVT and may provide a promising strategy for improving the functional outcomes in this patient population. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT06548971.

Early reocclusion is a significant contributor to early neurological deterioration and adverse outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis (IVT) therapy. Although current guidelines recommend delaying antithrombotic therapy until 24 h after IVT to reduce hemorrhagic risks, the persistently high incidence of reocclusion has prompted the exploration of earlier antithrombotic strategies. Despite theoretical benefits, extensive research has not consistently demonstrated the efficacy of early antithrombotic interventions. Nevertheless, a recent randomized controlled trial encouragingly demonstrated that ultra-early intravenous administration of the antiplatelet agent tirofiban after IVT was effective at improving functional outcomes in non-cardioembolic stroke patients with a low risk of hemorrhage. However, the considerable heterogeneity in both antithrombotic regimens and patient populations across existing studies has obscured the identification of beneficial candidates and intervention protocols for early post-thrombolysis antithrombotic therapy. We synthesizes the current evidence regarding patient selection, drug choice, and optimal timing for early antithrombotic therapy, to explore potential improvements in post-IVT antithrombotic management, emphasizing the critical need to balance the prevention of ischemic progression with the risk of hemorrhagic transformation.