Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1–STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions. Graphical abstract The schematic figure depicts a mechanism model of the STAT1–STING axis in HFpEF (this figure was drawn using FigDraw software).

Aims: A high red blood cell distribution width (RDW) at admission or discharge is associated with a worse prognosis in hospitalized patients with heart failure (HF), and the prognostic value of the in-hospital change in RDW (∆RDW) remains debatable. Methods and results: We included 5514 patients with critical illness and HF from the MIMIC-IV database. The ΔRDW was calculated by the RDW at discharge minus that at admission. Clinical outcomes included all-cause mortality at 90 day, 180 day, and 1 year after discharge. The median age of the patients was 73.91 years, and 46.37% were women. Kaplan–Meier curve and Cox regression analyses were used to examine the association between the ΔRDW and all-cause mortality at different time points. A multivariable Cox proportional hazard model showed that the ΔRDW (per 1% increase) was independently associated with all-cause mortality at 90 day, 180 day, and 1 year after adjusting for confounding factors (hazard ratio [HR] = 1.17, 95% confidence interval [CI] = 1.13–1.21, P < 0.001; HR = 1.17, 95% CI = 1.14–1.20, P < 0.001; and HR = 1.18, 95% CI = 1.15–1.20, P < 0.001, respectively). Restricted cubic splines showed a non-linear relationship between the ΔRDW and the risk of clinical outcomes. High ΔRDW was associated with a high risk of mortality at different time points. A subgroup analysis showed that this positive association remained consistent in pre-specified subgroups. Conclusions: Our study suggests that an increased RDW during hospitalization is independently associated with short- or long-term all-cause mortality in critical-ill patients with HF.

Aims Previous studies report that blood pressure (BP) variability is associated with increased risk of adverse outcomes in patients diagnosed with cardiovascular disease. However, studies have not fully explored this association in patients with heart failure with preserved ejection fraction (HFpEF). This study sought to explore the association between visit-to-visit variability (VVV) of BP and clinical outcomes in patients with HFpEF. Methods and results A total of 1988 patients (mean age of 67.73 ± 9.22, 51.7% female) from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were included in this study. BP-VVV was determined by standard deviation (SD) of mean systolic BP (SBP-SD) from six measurements (baseline and months 1, 2, 4, 8, and 12) during the first 12 months after randomization. Mean on-treatment SBP during the first 12 months was 127.77 ± 10.42 mmHg, and the median of SBP-SD was 8.15 mmHg. A total of 192 (9.7%) patients met the primary outcome during the subsequent median follow-up of 35.16 months, including a composite of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest. Multiple Cox regression analysis showed that SBP-SD was independently associated with the increased risk of the primary outcome after adjusting for age, gender, method of BP measurement, treatment, renal function and common co-morbidities, and the mean SBP during the first 12 months [hazard ratio (HR) for fourth vs. first quartile, 1.63; 95% confidence interval (CI), 1.07–2.49; P = 0.024]. Analysis showed that SBP-SD as continuous variable was associated with a 23% increase in the risk of primary outcome (HR 1.23, 95% CI 1.06–1.43; P = 0.006). Conclusions The findings of the current study show that high SBP-VVV in patients with HFpEF is associated with an increased risk of adverse outcomes independent of the mean on-treatment SBP.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to inhibit pyroptosis and apoptosis, which play important roles in the development and progression of contrast-induced acute kidney injury (CI-AKI). However, to the best of our knowledge, no studies have investigated the potential effect of PCSK9 inhibitors on the prevalence of CI-AKI after percutaneous coronary intervention (PCI). This study aimed to determine whether PCSK9 inhibitors are associated with the prevalence of CI-AKI. The medical records of 309 (mean age, 63.35 years; 71.84% male) patients with acute myocardial infarction who underwent PCI at our institution were retrospectively analyzed. Overall, 149 and 160 patients were assigned to the evolocumab and control groups, respectively. Serum creatinine levels were examined preoperatively and 24–72 h postoperatively and compared between groups. Data were grouped according to the occurrence of CI-AKI, and a univariate analysis was conducted to exclude suspected influencing factors that led to CI-AKI occurrence. After adjusting for confounding factors, a logistic regression analysis was performed to assess the association between evolocumab administration (independent variable) and CI-AKI occurrence (dependent variable). The prevalence of CI-AKI was significantly lower in the evolocumab group (6.7%) than in the control group (20.0%; ). We further evaluated the correlation between exposure factor and outcome. The relative risk(RR) between the use of evolocumab and the occurrence of CI-AKI was 0.34(95% CI 0.17-0.66,p<0.01).This result indicate a significant association between the use of evolocumab and a reduction in the incidence of CI-AKI.The logistic regression analysis results revealed that evolocumab was significantly associated with CI-AKI. The use of PCSK9 inhibitors, hydration therapy, and statin administration appears promising for preventing CI-AKI in patients with acute myocardial infarction undergoing PCI.

The aim of this paper is to discover differentially expressed genes related to ferroptosis (DEFRGs) in patients with ST-segment elevation myocardial infarction (STEMI) and to construct a reliable prognostic signature that incorporates key DEFRGs and easily accessible clinical factors. We did a systematic review of Gene Expression Omnibus datasets and picked datasets SE49925, GSE60993, and GSE61144 for analysis. We applied GEO2R to find DEFRGs and overlapped them among the picked datasets. We performed functional enrichment analysis to explore their biological functions. We built an optimal model with least absolute shrinkage and selection operator (LASSO) penalized Cox proportional hazards regression. We tested the clinical value of the signature with survival analysis, ROC curve, decision curve analysis and a prognostic nomogram. We also confirmed the model externally with plasma samples from our center's patients. A prognostic signature combining three overexpressed DEFRGs (ACSL1, ACSL4, TSC22D3) and two clinical variables (serum creatinine level, Gensini score) was established. The signature effectively classified patients into low- and high-risk groups. Survival analysis, ROC curve analysis, and DCA showed its robust predictive performance and clinical utility of the signature within two years after the onset of the disease. The external validation cohort confirmed the significant difference in major adverse cardiovascular events (MACEs) between the low- and high-risk groups. This study revealed DEFRGs in patients with STEMI and developed a prognostic signature that integrates gene expression levels and clinical factors for stratifying patients and predicting the risk of MACEs.