BackgroundBoth sodium-glucose co-transporter-2 (SGLT-2) inhibitors and angiotensin receptor-neprilysin inhibitor (ARNI) were recommended to treat heart failure with reduced ejection fraction (HFrEF). However, no trial was conducted to assess the efficacy and safety of the combined therapy of SGLT-2 inhibitors and ARNI in patients with HFrEF.MethodsWe performed a meta-analysis of the prespecified subgroups from DAPA-HF and EMPEROR-Reduced trials. The primary endpoint was the composite risk of cardiovascular death or hospitalization for heart failure. The risk of cardiovascular death, all-cause death, a composite of serious adverse renal outcomes, and volume depletion were also estimated.ResultsThe risk of the composite of cardiovascular death or hospitalization for heart failure was reduced in combined therapy of SGLT-2 inhibitors and ARNI, compared with ARNI monotherapy (RR.68, 95% CI.53 to.85, P = 0.001). When compared with SGLT-2 inhibitors monotherapy, the events of cardiovascular death (RR.64, 95% CI.46 to 0.87, P = 0.005) and all-cause death (RR.72, 95% CI.55 to.94, P = 0.01) were significantly less in combined therapy, accompanied by elevated incidence of volume depletion (RR 1.55, 95% CI 1.22 to 1.96, P = 0.0003).ConclusionCombined therapy has additional benefits over monotherapy in patients with HFrEF, however, it is accompanied by a possibly higher risk of volume depletion.
Aims: Vascular Calcification (VC) is recognized as an independent predictor of cardiovascular events. Estrogen replacement was reported as protective treatment against vascular calcification in postmenopausal women, while it is controversial because of its potential carcinogenicity. ERα co-regulators have been putatively considered as potential therapeutic targets for ERα-related cancers. However, the modulation of ERα action and biological function of ERα co-regulators in vascular calcification are still elusive. Methods and Results: KDM4B (Histone lysine demethylases 4B) was identified to be highly expressed in β-phosphoglycerol treated human and mouse aortic smooth muscle cells (ASMCs) and VitD3-overloaded mice during calcification by Western blot and immunofluorescence staining. Co-immunoprecipitation (Co-IP) and confocal immunofluorescence imaging were performed to show the association between KDM4B and ERa. Luciferase reporter assay demonstrated that KDM4B downregulated ERa-induced transactivation, and qPCR results showed that KDM4B depletion increased mRNA expression of endogenous ERa target gene; the results by co-IP showed that KDM4B associated with PRC2 complex and ERa. ChIP assay (Chromatin immunoprecipitation) demonstrated that KDM4B depletion decreased the recruitment of PRC2 (Polycomb repressive complex 2) complex to estrogen response element (ERE) regions, thereby down-regulating the level of H3K27me3. Finally, KDM4B-mediated enhancement of ASMCs calcification was attenuated by the estrogen treatment. Conclusion: KDM4B inhibits ERα-induced transactivation independent of its JmjC enzyme active region. KDM4B is involved in vascular calcification via down-regulation of ERα action. KDM4B associates with PRC2 complex to be recruited to ERE element of ERα downstream target gene, thereby modulating histone H3K27me3 modification on the ERE region, suggesting KDM4B acts as a new potential therapeutic target for VC.
Objective Many researches have demonstrated the effects of the extreme cold ambient temperature on the risk of out-of-hospital cardiac arrest (OHCA); yet, the results have been inconsistent. We performed a meta-analysis to evaluate whether extreme cold ambient temperature is related to OHCA. Methods We searched for time-series studies reporting associations between extreme cold ambient temperature and OHCA in PubMed, web of science and Cochrane database. Results Six studies involving 2 337 403 cases of OHCA were qualified for our meta-analysis. The odds ratio (OR) of OHCA was significantly increased in extreme cold weather (defined as the 1st or 5th centile temperature year-round) compared to reference temperature (as the 25th centile temperatures or daily mean temperature with minimum risk of OHCA) (OR=1.49, 95% CI 1.18–1.88). The subgroup analysis for the elderly and the female failed to detect the influence of extreme cold weather on OHCA, the ORs are 1.25 (95% CI 0.89–1.75) and 1.19 (95% CI 0.87–1.64), respectively. Conclusion The risk of OHCA is significantly higher in extreme cold ambient temperatures than in reference temperature, according to a relative temperature scale with percentiles of the region-specific temperature distribution.
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