RESUMO
Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well-characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A-driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.
RESUMO
AIMS: This systematic review and meta-analysis aimed to investigate the association between serum uric acid (SUA) levels and the incidence rate and prognosis of heart failure (HF), as well as the impact of uric acid-lowering treatment on HF patients. METHODS AND RESULTS: PubMed and Embase were searched for original articles reporting on the association between SUA and HF incidence, adverse outcomes, and the effect of uric acid-lowering treatment in HF patients. Data were pooled using random effects or fixed effects models. Univariable meta-regression analysis assessed the influence of study characteristics on research outcomes. Statistical analyses were conducted using RevMan software and STATA software version 15.0. Eleven studies on HF incidence and 24 studies on adverse outcomes in HF patients were included. Higher SUA levels were associated with an increased risk of HF (RR: 1.81, 95% CI: 1.53-2.16), all-cause mortality (RR: 1.44, 95% CI: 1.25-1.66), cardiac death (RR: 1.56, 95% CI: 1.32-1.84), and HF rehospitalization (RR: 2.07, 95% CI: 1.37-3.13) in HF patients. Uric acid-lowering treatment was found to increase all-cause mortality in HF patients (RR: 1.15, 95% CI: 1.05-1.25). CONCLUSIONS: Uric acid is an independent predictor of heart failure occurrence and adverse prognosis. Targeting uric acid lowering as a therapeutic intervention does not improve the prognosis of patients with heart failure. It may not be advisable to use traditional urate-lowering drugs in young patients with heart failure, and elderly patients should exercise caution when using them.
