Prognostic value of growth differentiation factor-15 in heart failure among whole ejection fraction phenotypes.

AIMS: The utility of growth differentiation factor-15 (GDF-15) in predicting long-term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF-15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF-15 into the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score-based model. METHODS AND RESULTS: This single-centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid-range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0 years (range: 56.0-77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF-15 concentration (P = 0.002) and a higher MAGGIC risk score (P < 0.001). We examined the associations between GDF-15 levels and the risks of all-cause mortality and HF rehospitalization using Cox regression models. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4 year follow-up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF-15 levels were significantly associated with an increased risk of all-cause mortality [hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.20-1.54; P < 0.001] and HF rehospitalization (HR = 1.75, 95% CI: 1.57-1.95; P < 0.001) across all HF phenotypes. This association remained significant when GDF-15 was treated as a categorical variable (high GDF-15 group: all-cause death: HR = 1.73, 95% CI: 1.40-2.14; P < 0.001; HF rehospitalization: HR = 3.37, 95% CI: 2.73-4.15; P < 0.001). Inclusion of GDF-15 in the MAGGIC risk score-based model provided additional prognostic value for all HF patients (Δ C-index = 0.021, 95% CI: 0.002-0.041; IDI = 0.011, 95% CI: 0.001-0.025; continuous NRI = 0.489, 95% CI: 0.174-0.629) and HF rehospitalization (Δ C-index = 0.034, 95% CI: 0.005-0.063; IDI = 0.021, 95% CI: 0.007-0.032; continuous NRI = 0.307, 95% CI: 0.147-0.548), particularly in the HFpEF subgroup. CONCLUSIONS: GDF-15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF-15 into the MAGGIC risk score-based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups.

Effects of cigarette smoking on older chinese men treated with clopidogrel monotherapy or aspirin monotherapy: a prospective study.

We investigated the comparative effects of smoking status on outcomes in older Chinese men receiving aspirin or clopidogrel monotherapy. This was a prospective observational study of outcomes in 668 men aged ≥ 60 years undergoing annual health examination in the Chinese People's Liberation Army General Hospital from March-April 2017. All patients received regular treatment with aspirin or clopidogrel. Platelet aggregation and phenotyping for rs762551 were measured in all patients. We recorded all major adverse cardiovascular and cerebrovascular events; namely, all-cause death, myocardial infarction, stroke, transient ischemic attack, and unstable angina. In the clopidogrel subgroup, homozygous carriers (AA) of the CYP1A2*1F gene (rs762551, 163C>A) appeared more frequently in smokers than in nonsmokers (45.6% vs 32.7%, p = .035). Adenosine diphosphate-induced platelet aggregation using light transmittance aggregometry was lower in smokers compared with nonsmokers (44.97 ± 20.05% vs 51.98 ± 19.38%, respectively; p = .0018). Smokers (n = 103) had a decreased risk of major adverse cardiovascular and cerebrovascular events, compared with nonsmokers [n = 159; hazard ratio, 0.466; 95% confidence interval: 0.262-0.829, p = .008]. In the aspirin subgroup, AA-induced platelet aggregation showed no significant difference regarding smoking vs nonsmoking status (30.90 ± 32.21 vs 29.78 ± 31.47, respectively; p = .771). However, we saw a significant increase in adverse clinical events in the smoking group (n = 148) compared with the nonsmoking group (n = 258; hazard ratio = 1.907, 95% confidence interval: 1.128-3.225; p = .016). In older Chinese men, active smokers benefitted from clopidogrel therapy compared with aspirin. Long-term cigarette smoking may contribute to increased variations in CYP1A2*1F, but the variations do not fully explain the smoking paradox.

Effects of Ethyl Pyruvate in Preventing the Development of Diet-induced Atherosclerosis by Blocking the HMGB1 Expression in ApoE-Deficient Mice.

Ethyl pyruvate (EP) is a lipid derivative of pyruvate and known as an anti-inflammatory agent effective to inhibit many diseases in experimental models. To test the hypothesis that Ethyl pyruvate might prevent atherosclerosis development by blocking the high-mobility group box-1 (HMGB1) expression, 8-week-old ApoE-deficient (ApoE-/-) mice were fed a high-fat diet and treated with EP (50 mg/Kg) or Physiological saline for 12 weeks. THP-1 cells were then differentiated into macrophages by treated with Phorbol-12-myristate-13-acetate (PMA, 100 ng/mL) and incubated with oxidized low-density lipoprotein (oxLDL) only or added with EP (5 mM) for 24 hour. In ApoE-/- mice, EP markedly reduced aortic sinus atherosclerosis lesions with no influence to serum lipid levels. Inhibited HMGB1 expression, decreased macrophages content and reduced Toll-like-receptor2 (TLR2), TLR4, monocyte chemotactic protein 1 (MCP-1) and Tumor Necrosis Factor α (TNF-α) mRNA levels were also observed at the same time. In vitro, EP decreased oxLDL uptake in macrophages and inhibited HMGB1 expression induced by oxLDL. In conclusion, our study indicated that EP was an effective agent against the development of diet-induced atherosclerosis in ApoE-deficient mice by way of blocking the HMGB1 expression.