BACKGROUND: Patients with renal dysfunction remain at high risk for contrast-associated acute kidney injury despite standard peri-procedural volume administration. This study aims to investigate whether peri-procedural oral nicorandil provides additional protection in this population, and to evaluate its potential dose-response relationship. METHODS: We conducted a prospective, multicenter, randomized controlled trial enrolling patients with percutaneous coronary intervention with renal dysfunction. Participants were randomized into 3 groups, including a high-dose nicorandil group (30 mg/d, 10 mg 3× daily), a conventional-dose nicorandil group (15 mg/d, 5 mg 3× daily), and a saline hydration-only control group. The primary end point was the incidence of contrast-associated acute kidney injury. Secondary end points included changes in serum creatinine, blood urea nitrogen, CysC (cystatin C), and CRP (C-reactive protein). RESULTS: A total of 585 patients were recruited and randomized. The incidence of contrast-associated acute kidney injury was significantly lower in both nicorandil groups, with 19.8% (39/197) in the control group, compared with 10.9% (21/193) in the conventional-dose group and 8.7% (17/195) in the high-dose group ( P <0.001). This represented a relative risk reduction of 50% and 61% for the conventional- and high-dose groups, respectively. CONCLUSIONS: Adjunctive nicorandil, particularly at a dose of 10 mg 3× daily, significantly reduced the incidence of contrast-associated acute kidney injury in percutaneous coronary intervention patients with renal dysfunction. Oral nicorandil represents a readily available, effective, and dose-dependent prophylactic strategy to enhance renoprotection. Future studies are warranted to evaluate the long-term clinical benefits of this intervention. REGISTRATION: URL: https://www.chictr.org.cn ; Unique identifier: CTR2200064264.

Introduction: Myocardial fibrosis, characterized by excessive extracellular matrix deposition, leading to adverse cardiac remodeling and impaired function. The differentiation of cardiac fibroblasts into myofibroblasts plays a pivotal role in this process. The involvement of the core clock protein CLOCK in the formation of cardiac myofibroblasts and the advancement of myocardial fibrosis is not well understood. This study aims to investigate how CLOCK modulates cardiac myofibroblast differentiation and attenuates myocardial fibrosis by inhibiting Smad3 transcriptional activity. Methods: In vivo, adeno-associated virus 9 was utilized for overexpression or silencing of the CLOCK gene via mice intravenous injection. In vitro experiments were conducted using primary cultures of cardiac fibroblasts isolated from mouse hearts to examine the expression levels of molecular markers associated with myofibroblast differentiation, such as α-smooth muscle actin (α-SMA) and collagen I. Additionally, a Smad3 luciferase reporter gene experiment was employed to assess the transcriptional activity of Smad3 under CLOCK regulation. Results: The results demonstrate that CLOCK overexpression significantly reduces the expression of α-SMA and collagen I in cardiac fibroblasts, indicating a suppression of myofibroblast formation. Conversely, CLOCK knockdown enhances the expression of these fibrotic markers. Interestingly, CLOCK was found to negatively regulate the transcriptional activity of Smad3, suggesting a potential mechanism by which CLOCK exerts its inhibitory effect on cardiac fibrosis. Specifically, CLOCK interacts with Smad3, inhibiting its nuclear translocation and subsequent activation of fibro genic gene expression. Conclusion: These findings highlight the crucial role of CLOCK in the regulation of cardiac myofibroblast formation and the progression of myocardial fibrosis. CLOCK appears to exert an inhibitory effect on fibrotic signaling pathways, partially through the inhibition of Smad3 transcriptional activity. This study provides novel insights into the molecular mechanisms underlying cardiac fibrosis and emphasizes the therapeutic potential of targeting CLOCK-mediated pathways for treating myocardial fibrosis.

Background: The prognostic value of discharge renin–angiotensin–aldosterone system inhibitor (RASi) therapy in contemporary PCI-treated acute myocardial infarction (AMI) survivors with preserved or mildly reduced left ventricular ejection fraction (LVEF) remains uncertain. Methods: A retrospective cohort study of 2530 AMI patients (2019–2022) stratified by RASi use. Exclusion criteria were in-hospital mortality, LVEF < 40%, contraindications to the use of RASis or no percutaneous coronary intervention (PCI). Primary endpoints included heart failure (HF) events, recurrent acute coronary syndrome (ACS), and all-cause mortality. Kaplan–Meier analyses and inverse probability of treatment weighting (IPTW)-weighted Cox models were applied. Results: Over a mean follow-up of 49 months, discharge RASi therapy was not associated with all-cause mortality overall, but was associated with fewer HF rehospitalizations (HR 0.62, 95% CI 0.40–0.95; p = 0.03). Mortality associations differed by AMI type and hypertension status, particularly for NSTEMI (HR 0.36, 95% CI 0.14–0.91; p = 0.03; p for interaction = 0.02) and hypertension (HR 0.36, 95% CI 0.15–0.84; p = 0.02; p for interaction = 0.04). Conclusions: In this single-center observational cohort of PCI-treated AMI survivors with LVEF ≥ 40%, discharge RASi therapy was associated with fewer HF rehospitalizations but not with lower overall mortality. Exploratory subgroup analyses suggested potential heterogeneity according to NSTEMI status and hypertension, but these findings should be considered hypothesis-generating and require confirmation.