Study Objective: Obstructive sleep apnea is prevalent among people with asthma, but underlying mechanisms remain unknown. Inhaled corticosteroids may contribute. We tested the effects of orally inhaled fl uticasone propionate (FP) on upper airway (UAW) during sleep and wakefulness. Study design: 16-week single-arm study. Participants: 18 (14 females, mean [ ± SD] age 26 ± 6 years) corticosteroid-naïve subjects with mild asthma (FEV 1 89 ± 8% predicted). Interventions: High dose (1,760 mcg/day) inhaled FP. Measurements: (1) UAW collapsibility (passive critical closing pressure [Pcrit]); (2) tongue strength (maximum isometric pressure-Pmax, in KPa) and endurance-time (in seconds) able to maintain 50% Pmax across 3 trials (Ttot)-at anterior and posterior locations; (3) fat fraction and volume around UAW, measured by magnetic resonance imaging in three subjects. Results: Pcrit overall improved (became more negative) (mean ± SE) (-8.2 ± 1.1 vs. -12.2 ± 2.2 cm H 2 O, p = 0.04); the response was dependent upon baseline characteristics, with older, male gender, and worse asthma control predicting Pcrit deterioration (less negative). Overall, Pmax increased (anterior p = 0.02; posterior p = 0.002), but Ttot generally subsided (anterior p = 0.0007; posterior p = 0.06), unrelated to Pcrit response. In subjects studied with MRI, fat fraction and volume increased by 20.6% and 15.4%, respectively, without Pcrit changes, while asthma control appeared improved. Conclusions: In this study of young, predominantly female, otherwise healthy subjects with well-controlled asthma and stiff upper airways, 16-week high dose FP treatment elicited Pcrit changes which may be dependent upon baseline characteristics, and determined by synchronous and reciprocally counteracting local and lower airway effects. The long-term implications of these changes on sleep disordered breathing severity remain to be determined. S C I E N T I F I C I N V E S T I G A T I O N SG rowing evidence suggests that asthma patients have an increased predisposition for obstructive sleep apnea (OSA). Studies consistently fi nd higher prevalence of OSA symptoms among asthma patients.1-5 In a 14-year longitudinal study, asthma emerged as an independent risk factor for incident habitual snoring when adjusting for relevant confounders, including body mass index (BMI) at baseline and its change in time.6 Likewise, the prevalence of OSA diagnosed on polysomnography (PSG) is high (88% to 95.5%) in diffi cult-to-control asthma, 7,8 and follows asthma severity with 58% in moderate asthma versus 12% in controls. 7The mechanisms underlying this increased risk for OSA in asthma remain unknown. Apart from traditional OSA risk factors, BRIEF SUMMARYCurrent Knowledge/Study Rationale: Obstructive sleep apnea is more prevalent among people with asthma of increasing severity, but underlying mechanisms remain unknown. Inhaled corticosteroids may play a role. Study Impact: Sixteen-week treatment with inhaled fl uticasone elicited individual responses in upper airway collapsibility depe...

Background The intrauterine environment strongly influences adult disease susceptibility. We utilized a rat model of third trimester maternal diabetes to test the hypothesis that adult offspring exposed to hyperglycemia in utero display increased blood pressure and alterations in vascular responsiveness. Methods Diabetes was induced by streptozotocin injection to pregnant rats on gestation day 13 (term 21 day) and partially controlled with insulin injections. Hemodynamic function was evaluated in 6–12 month old offspring. Results Male but not female offspring of diabetic mothers (ODM) had significantly increased blood pressure compared to controls, heart rate was similar. For both sexes, heart rate baroreflex responses were similar as were in vivo hemodynamic responses to angiotensin II, NOS inhibition and ganglionic blockade. Aortic contractility to angiotensin II was similar in both groups. NOS inhibition and the Cu/Zn superoxide dismutase (SOD) inhibitor diethyldithiocarbamate but not the SOD-mimetic Tempol significantly increased contractile responses to angiotensin II in controls but not ODM. NADPH stimulated superoxide production was greater in male ODM than controls (p<0.05). Conclusions Exposure to hyperglycemia in utero results in sex specific cardiovascular changes in adult offspring. Impaired NO - reactive oxygen species signaling may play a significant role in the hemodynamic phenotype of ODM.

Background Angiotensin II (ANG II) stimulates fetal heart growth, though little is known regarding changes in cardiomyocyte endowment or the molecular pathways mediating the response. We measured cardiomyocyte proliferation and morphology in ANG II treated fetal sheep and assessed transcriptional pathway responses in ANG II and losartan (an ANG II type 1 receptor antagonist) treated fetuses. Methods In twin gestation pregnant sheep, one fetus received ANG II (50 μg/kg/min iv) or losartan (20 mg/kg/d iv) for 7 days; non-instrumented twins served as controls. Results ANG II produced increases in heart mass, cardiomyocyte area (left ventricle (LV) and right ventricle mononucleated and LV binucleated cells) and the percentage of Ki-67-positive mononucleated cells in the LV (all p< 0.05). ANG II and losartan produced generally opposing changes in gene expression, affecting an estimated 55% of the represented transcriptome. The most prominent significantly effected biological pathways included those involved in cytoskeletal remodeling and cell cycle activity. Conclusion ANG II produces an increase in fetal cardiac mass via cardiomyocyte hypertrophy and likely hyperplasia, involving transcriptional responses in cytoskeletal remodeling and cell cycle pathways.

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