The Effect of 17beta Estradiol on Glut1 Expression In The Right Ventricle Of Rats With Severe Pulmonary Hypertension

poster abstractPulmonary hypertension (PH) is a devastating disease that is characterized by a rise of blood pressure in the blood vessels of the lung. This puts significant strain on the right ventricle (RV) of the heart. If untreated, PH can lead to right heart failure and death. One of the hallmarks of right heart failure in PH is the development of cytoplasmic glycolysis in the cardiac muscle cells (myocytes) of the RV. This describes a compensatory process where glucose uptake into the mitochondria is inhibited, thereby leading to its conversion to lactate in the cytoplasm. Importantly, cytoplasmic glycolysis is associated with an increase in a protein called glucose transporter 1 (Glut 1). 17beta estradiol (E2) can ameliorate experimental PH, but its effects on RV glut 1 expression are not yet known. The aim of this project is to determine the RV expression of Glut 1 in a rat model of severe PH, and to investigate whether this is decreased by E2 treatment. We assessed Glut 1 via immunofluorescence staining in cryosections of RV tissue from control rats, untreated PH rats, and E2-treated PH rats. Cell nuclei were stained with DAPI (Diamidinophenyl-indole), cell membranes were stained with WGA (wheat germ agglutinin), and Glut1 was stained with a Glut1 antibody conjugated to a red immunofluorescent dye. Nuclei are stained blue; cell membranes are stained green. Glut 1 quantification occurs via visual inspection and determination of red staining via specific software (Metamorph). We were able to successfully establish the protocol for Glut1 staining. In pilot experiments, there was little Glut1 staining present in normal RVs, but we detected up-regulation of Glut 1 in the RV of animals with PH. Whether this is affected by E2 is currently under investigation

A patient with severe hypoxia secondary to a large iatrogenic pulmonary artery to pulmonary vein fistula.

Pulmonary arteriovenous malformations are uncommon communications between the pulmonary arteries and veins, most commonly associated with hereditary haemorrhagic telangiectasia. They can also be associated with a variety of other conditions, and can be single or multiple. We present a case of a female patient with a history of coronary artery bypass grafting and mitral valve repair, who presented to the hospital with severe hypoxia. She was found to have a large pulmonary artery to superior pulmonary vein fistula that was successfully repaired using a septal occluder. To our knowledge, this is the first case of a large pulmonary artery to superior pulmonary vein fistula following mitral valve repair

Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones

Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2’s RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 μg·kg−1·day−1). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL-6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (V̇o2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERα in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERα expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERα or ERβ agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH

Efficacy of bendamustine and rituximab in unfit patients with previously untreated chronic lymphocytic leukemia. Indirect comparison with ibrutinib in a real-world setting. A GIMEMA-ERIC and US study.

Limited information is available on the efficacy of front-line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real-world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty-seven patients with creatinine clearance (CrCl)/min and/or CIRS score \u3e6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression-free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02-1.10, P \u3c 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33-0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage