Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Development and Validation of a Novel Nomogram to Predict the Impact of the Polymorphisms of the Variants of ICAM-1 Gene on the Prognosis of Ischemic Cardiomyopathy

Tuersunjiang Naman,* Refukaiti Abuduhalike,* Aihaidan Abudouwayiti, Juan Sun, Ailiman Mahemuti Department of Heart Failure, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ailiman Mahemuti, Department of Heart Failure, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China, Email [email protected]: This study investigated the correlation between polymorphisms of the ICAM-1 gene and prognosis of Ischemic cardiomyopathy (ICM), and developed a prognostic model for predicting the prognosis ICM on the basis of ICAM-1 gene variants.Methods: The current study included totally 576 patients with ICM. All patients are randomly divided into training group with 399 patients and validation group with 177 patients. The prognostic model was constructed by using the data of training group. Univariable Cox-regression analysis was performed, including clinical and gene variants, then used the least absolute shrinkage and selection operator (LASSO) regression model to optimize feature selection. Furthermore, multivariate Cox-regression was applied to build the prognostic nomogram model, which included clinical and gene features chosen by the LASSO regression model. Following that, the receiver operating characteristic (ROC) curve, C-index, calibration plot analyses and decision curve analysis (DCA) were carried out to evaluate the discrimination ability, consistency, and clinical utility of the prognostic model.Results: Predicting factors rs281430, ventricular arrhythmia, treating by PCI or CABG, use of β-blockers, heart rate (HR), serum sodium level, left ventricular end-diastolic diameter (LVDD) were the risk factors of the prognosis of ICM, incorporated these factors into the prognostic nomogram model. The constructed nomogram performed well in discrimination ability, as observed by the ROC and C-index. Furthermore, as shown by calibration curves, our nomogram’s predicted probabilities were highly consistent with measured values. With threshold probabilities, DCA suggested that our nomogram could be useful in the clinic.Conclusion: rs281430 mutation (from AA genotype to AG or GG genotype) is a risk factor for ICM patients to have a higher survival probability; the survival probability of ICM patients with the mutant genotype (AG or GG) is lower than those with the wild genotype (AA).Keywords: gene polymorphism, ICAM-1 gene variants, ischemic cardiomyopathy, ICM, prognostic model, risk factors for prognosis of IC

Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts

Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction. Exposure to 100 μM BPA had no effects on cell viability, but increased cytoplasmic expression of ERβ and release of GDF-15, as well as decreased release of IL-6, ET-1, and IP-10 through suppression of NFκB phosphorylation. By performing global gene expression and pathway analysis in this study, we identified molecular pathways, gene networks, and key molecules that were affected by 100, but not 0.01 and 1 µM BPA in HFLF. Using multiple genomic and proteomic tools, we confirmed these changes at both gene and protein levels. Our data suggest that 100 μM BPA increased CYP1B1 and HSD17B14 gene and protein expression and release of endogenous estradiol, which was associated with increased ROS production and DNA double-strand breaks, upregulation of genes and/or proteins in steroid synthesis and metabolism, and activation of Nrf2-regulated stress response pathways. In addition, BPA activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence and autophagy, and decreased cell proliferation in HFLF. The results suggest that prenatal exposure to BPA at certain concentrations may affect fetal lung development and maturation, and thereby affecting susceptibility to childhood respiratory diseases