digoxin and Weight-Gain

Digoxin has been associated with lower interstage mortality (ISM) following stage 1 palliation (S1P). Despite a substantial increase in digoxin use nationally, ISM has not declined. We aimed to determine the impact of digoxin on ISM in the current era. This study analyzed data from the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) registry. All patients who survived to hospital discharge following S1P were included. Comparisons were made between pre-specified eras (1: 2010-2015, 2: 2016-2019) based on digoxin use. ISM risk was estimated using the previously published NEONATE score (excluding digoxin). Multivariable Cox proportional hazard models assessed the impact of digoxin on ISM and freedom from unplanned readmission in era 2. A total of 1400 (46.8%) patients were included from era 1 and 1589 (53.2%) from era 2. Digoxin use (22.4% vs 61.7%, p < 0.001) and the proportion of high-risk patients (9.1% vs 20.3%, p < 0.001) increased across eras. There was no difference in predicted ISM risk between those who did vs did not receive digoxin in era 2 (p = 0.82). In era 2, digoxin use was independently associated with lower ISM (AHR 0.60, 95%CI 0.36 to 0.98, p = 0.043) and greater freedom from unplanned readmission (AHR 0.44, 95%CI 0.32 - 0.59, p < 0.001). In conclusion, digoxin is independently associated with lower ISM and greater freedom from interstage readmission. The lack of improvement in overall ISM in the current era may be secondary to a greater proportion of high-risk patients and/or disproportionately higher digoxin use in lower risk patients, who may not derive the same benefit.

Topics: Cardiotonic Agents; Digoxin; Female; Heart Defects, Congenital; Humans; Hypoplastic Left Heart Syndrome; Infant; Infant, Newborn; Male; Mortality; Norwood Procedures; Patient Readmission; Postoperative Care; Registries; Weight Gain

Hypoxia-inducible factor 1α (HIF1α) induction in adipocytes is a critical component of the "fibrotic response," directly linked to metabolic dysfunction in adipose tissues under hypoxic conditions. We reasoned that inhibition of HIF1α may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1α inhibitor PX-478, whose effectiveness has previously been established in tumor models. We demonstrate that PX-478 treatment effectively suppresses the high-fat-diet (HFD)-induced HIF1α activation in adipose tissue. HIF1α inhibition causes a reduction of weight gain in mice on an HFD but not on a chow diet. Treatment increases energy expenditure and prompts resistance to HFD-mediated deterioration of metabolic parameters. Moreover, PX-478-treated mice have reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. We confirm the metabolic effects obtained with PX-478 treatment using an adipose tissue-specific, doxycycline-inducible dominant negative HIF1α mutant (dn-HIF1α). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1α activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1α inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1α inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Digoxin; Energy Metabolism; Fatty Liver; Glucose Tolerance Test; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mustard Compounds; Mutation; Oxygen; Phenylpropionates; Up-Regulation; Weight Gain