Association Between Preexisting Heart Failure With Reduced Ejection Fraction and Fluid Administration Among Patients With Sepsis.

Importance: Intravenous fluid administration is recommended to improve outcomes for patients with septic shock. However, there are few data on fluid administration for patients with preexisting heart failure with reduced ejection fraction (HFrEF). Objective: To evaluate the association between preexisting HFrEF, guideline-recommended intravenous fluid resuscitation, and mortality among patients with community-acquired sepsis and septic shock. Design, Setting, and Participants: A cohort study was conducted of adult patients hospitalized in an integrated health care system from January 1, 2013, to December 31, 2015, with community-acquired sepsis and preexisting assessment of cardiac function. Follow-up occurred through July 1, 2016. Data analyses were performed from November 1, 2020, to August 8, 2022. Exposures: Preexisting heart failure with reduced ejection fraction (≤40%) measured by transthoracic echocardiogram within 1 year prior to hospitalization for sepsis. Main Outcomes and Measures: Multivariable models were adjusted for patient factors and sepsis severity and clustered at the hospital level to generate adjusted odds ratios (aORs) and 95% CIs. The primary outcome was the administration of 30 mL/kg of intravenous fluid within 6 hours of sepsis onset. Secondary outcomes included in-hospital mortality, intensive care unit admission, rate of invasive mechanical ventilation, and administration of vasoactive medications. Results: Of 5278 patients with sepsis (2673 men [51%]; median age, 70 years [IQR, 60-81 years]; 4349 White patients [82%]; median Sequential Organ Failure Assessment score, 4 [IQR, 3-5]), 884 (17%) had preexisting HFrEF, and 2291 (43%) met criteria for septic shock. Patients with septic shock and HFrEF were less likely to receive guideline-recommended intravenous fluid than those with septic shock without HFrEF (96 of 380 [25%] vs 699 of 1911 [37%]; P < .001), but in-hospital mortality was similar (47 of 380 [12%] vs 244 of 1911 [13%]; P = .83). In multivariable models, HFrEF was associated with a decreased risk-adjusted odds of receiving 30 mL/kg of intravenous fluid within the first 6 hours of sepsis onset (aOR, 0.63; 95% CI, 0.47-0.85; P = .002). The risk-adjusted mortality was not significantly different among patients with HFrEF (aOR, 0.92; 95% CI, 0.69-1.24; P = .59) compared with those without, and there was no interaction with intravenous fluid volume (aOR, 1.00; 95% CI, 0.98-1.03; P = .72). Conclusions and Relevance: The results of this cohort study of patients with community-acquired septic shock suggest that preexisting HFrEF was common and was associated with reduced odds of receiving guideline-recommended intravenous fluids.

Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor.

Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting and degenerative disorders. Activin type IIB receptor (ActRIIB) is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of transforming growth factor (TGF)-ß family members including myostatin. To determine reliable and valid biomarkers for ActRIIB-Fc treatment, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared with mice genetically lacking myostatin and control mice. Expression of 134 genes was significantly altered in mice treated with ActRIIB-Fc over a 2-wk period relative to control mice (fold change > 1.5, P < 0.001), whereas the number of significantly altered genes in mice treated for 2 days was 38, demonstrating a time-dependent response to ActRIIB-Fc in overall muscle gene expression. The number of significantly altered genes in Mstn(-/-) mice relative to control mice was substantially higher (360), but for most of these genes the expression levels in the 2-wk treated mice were closer to the levels in the Mstn(-/-) mice than in control mice (P < 10⁻³°). Expression levels of 30 selected genes were further validated with quantitative real-time polymerase chain reaction (qPCR), and a correlation of ≥ 0.89 was observed between the fold changes from the microarray analysis and the qPCR analysis. These data suggest that treatment with ActRIIB-Fc results in overlapping but distinct gene expression signatures compared with myostatin genetic mutation. Differentially expressed genes identified in this study can be used as potential biomarkers for ActRIIB-Fc treatment, which is currently in clinical trials as a therapeutic agent for muscle wasting and degenerative disorders.

BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90.

Inhibition of heat shock protein 90 (Hsp90) results in the degradation of oncoproteins that drive malignant progression, inducing cell death, making Hsp90 a target of substantial interest for cancer therapy. BIIB021 is a novel, fully synthetic inhibitor of Hsp90 that binds competitively with geldanamycin in the ATP-binding pocket of Hsp90. In tumor cells, BIIB021 induced the degradation of Hsp90 client proteins including HER-2, AKT, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. BIIB021 treatment resulted in growth inhibition and cell death in cell lines from a variety of tumor types at nanomolar concentrations. Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models. Studies to investigate the antitumor effects of BIIB021 showed activity on both daily and intermittent dosing schedules, providing dose schedule flexibility for clinical studies. Assays measuring the HER-2 protein in tumor tissue and the HER-2 extracellular domain in plasma were used to show interdiction of the Hsp90 pathway and utility as potential biomarkers in clinical trials for BIIB021. Together, these data show that BIIB021 is a promising new oral inhibitor of Hsp90 with antitumor activity in preclinical models.