The β1-adrenergic antagonist metoprolol improves cardiac function in animals and patients with chronic heart failure, isolated mitral regurgitation (MR), and ischemic heart disease, though the molecular mechanisms remain incompletely understood. Metoprolol has been reported to upregulate cardiac expression of β3-adrenergic receptors (β3AR) in animal models. Myocardial β3AR signaling via neuronal nitric oxide synthase (nNOS) activation has recently emerged as a cardioprotective pathway. We tested whether chronic β1-adrenergic blockade with metoprolol enhances myocardial β3AR coupling with nitric oxide-stimulated cyclic guanosine monophosphate (β3AR/NO-cGMP) signaling in the MR-induced, volume-overloaded heart. We compared the expression, distribution, and inducible activation of β3AR/NO-cGMP signaling proteins within myocardial membrane microdomains in dogs (canines) with surgically induced MR, those also treated with metoprolol succinate (MR+βB), and unoperated controls. β3AR mRNA transcripts, normalized to housekeeping gene RPLP1, increased 4.4 × 103- and 3.2 × 102-fold in MR and MR+βB hearts, respectively, compared to Control. Cardiac β3AR expression was increased 1.4- and nearly twofold in MR and MR+βB, respectively, compared to Control. β3AR was detected within caveolae-enriched lipid rafts (Cav3+LR) and heavy density, non-lipid raft membrane (NLR) across all groups. However, in vitro selective β3AR stimulation with BRL37344 (BRL) triggered cGMP production within only NLR of MR+βB. BRL induced Ser1412 phosphorylation of nNOS within NLR of MR+βB, but not Control or MR, consistent with detection of NLR-specific β3AR/NO-cGMP coupling. Treatment with metoprolol prevented MR-associated oxidation of NO biosensor soluble guanylyl cyclase (sGC) within NLR. Metoprolol therapy also prevented MR-induced relocalization of sGCβ1 subunit away from caveolae, suggesting preserved NO-sGC-cGMP signaling, albeit without coupling to β3AR, within MR+βB caveolae. Chronic β1-blockade is associated with myocardial β3AR/NO-cGMP coupling in a microdomain-specific fashion. Our canine study suggests that microdomain-targeted enhancement of myocardial β3AR/NO-cGMP signaling may explain, in part, β1-adrenergic antagonist-mediated preservation of cardiac function in the volume-overloaded heart.

No abstract

No abstract

No abstract

INTRODUCTION: A common cause of iron (Fe) deficiency anemia (IDA) is gastrointestinal bleeding (GIB). While treatment is aimed at the underlying cause of IDA, it is also targeted at replenishing Fe stores to reduce anemia progression and end organ damage. Our objective was to assess whether patients hospitalized with IDA secondary to GIB received appropriate Fe supplementation upon discharge and the effect of this therapy post-discharge. METHODS: Retrospective review of patients hospitalized with GIB between 1/2017 and 12/2017. Patients eligible for Fe on discharge had one or more of the following: ferritin ≤30, Fe saturation ≤10%, and/or ≥2-gram decrease from the patient's baseline hemoglobin (hgb) with a final hgb of <10.0 due to GIB. We excluded patients with active malignancy, prior abdominal surgery, hematologic disorders, hgb > 10 on discharge, or died during hospitalization. We recorded the hgb on admission, nadir, and discharge and whether blood transfusions and Fe supplementation were given. In addition, use of anticoagulants and antiplatelet agents prior to admission was recorded. A post-discharge period of 180 days was used to assess outpatient hgb levels and hospital readmission. A regression analysis was performed to identify significant variables associated with receiving appropriate Fe supplementation on discharge. RESULTS: From 992 records, 228 patients met inclusion criteria. There were 115 M, 113 F, with a mean age of 62.6y. Overall, 106 (46.5%) patients received Fe on discharge. In regression analysis, adjusted for multiple confounders, having received Fe (PO or IV) while inpatient was strongly predictive of receiving Fe on discharge aOR= 13.5 (CI 6.8-26.8). In addition, if admission hgb was <8.0, the aOR of receiving Fe on discharge was 2.21 (CI 1.10 – 4.45). Nadir and discharge hemoglobin were not associated with Fe supplementation. There was no statistical reduction in readmission rates for those discharged on Fe although a Type 2 error could not be excluded. CONCLUSION: Physicians fail to provide Fe supplementation on discharge to over 50% of patients eligible after a GIB. Fe supplementation during a patient's hospitalization is the strongest predictor of receiving Fe upon discharge. This may be due to the medication reconciliation performed by the EMR at time of discharge. The other predictor variable was admission hgb but not nadir or discharge hgb. Automated reminders built into the EMR may help reduce this widespread problem.