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Background Pressure overload due to aortic stenosis (AS) causes maladaptive ventricular and vascular remodeling that can lead to pulmonary hypertension, heart failure symptoms, and adverse outcomes. Retarding or reversing this maladaptive remodeling and its unfavorable hemodynamic consequences has potential to improve morbidity and mortality. Preclinical models of pressure overload have shown that phosphodiesterase type 5 (PDE5) inhibition is beneficial, however the use of PDE5 inhibitors in patients with AS is controversial because of concerns about vasodilation and hypotension. Methods and Results We evaluated the safety and hemodynamic response of 20 subjects with severe symptomatic AS (mean aortic valve area 0.7±0.2 cm2, ejection fraction 60±14%) who received a single oral dose of sildenafil (40mg or 80mg). Compared to baseline, after 60 minutes sildenafil reduced systemic (−12%, p<0.001) and pulmonary (−29%, p=0.002) vascular resistance, mean pulmonary artery (−25%, p<0.001) and wedge (−17%, p<0.001) pressure, and increased systemic (+13%, p<0.001) and pulmonary (+45%, p<0.001) vascular compliance and stroke volume index (+8%, p=0.01). These changes were not dose dependent. Sildenafil caused a modest decrease in mean systemic arterial pressure (−11%, p<0.001), but was well-tolerated with no episodes of symptomatic hypotension. Conclusions This study shows for the first time that a single dose of a PDE5 inhibitor is safe and well-tolerated in patients with severe AS and is associated with acute improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading. These findings support the need for longer-term studies to evaluate the role of PDE5 inhibition as adjunctive medical therapy in patients with AS.

ObjectiveTo determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF).MethodsA primary cohort (N=12) with HFpEF and obesity underwent echocardiography, magnetic resonance spectroscopy before, and 3- and 6-mos after bariatric surgery. Plasma lipidomics were performed on pre- and 3-mo post-surgery in the primary cohort and confirmed in a validation cohort (N=22).ResultsAfter surgery-induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, < 0.001, = 0.007); echo-derived e′ increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate.ConclusionsSurgery-induced weight loss in women with HFpEF and obesity is associated with improved symptoms, reverse cardiac remodeling and improved relaxation. While weight loss associated with plasma sphingolipidome changes, cardiac function improvement was not associated with lipidomic or myocardial triglyceride changes. Our study results suggest that gastric bypass ameliorates obesity-related HFpEF and that cardiac fat deposition and lipidomic changes may not be critical to its pathogenesis.

Hypothalamic orexin-containing neurons project to many CNS targets, including motoneurons. We assessed developmental changes in the expression of the orexin type 2 receptor (ORX2r) mRNA in hypoglossal (XII) motoneurons. Identified motoneurons were dissociated from 4- to 33-day-old rats and subjected to single-cell reverse transcription and PCR; nearly all contained the ORX2r mRNA. In 40 motoneurons studied using semi-nested PCR, and in another 39 subjected to quantitative, real-time PCR, the number of reverse-transcribed mRNA copies per cell was significantly higher around day 20 postnatally than at any other age. Thus, ORX may postsynaptically excite XII motoneurons, with the ORX2r mRNA production increased during the critical period for development of the rapid eye movement sleep and its disorder narcolepsy/cataplexy.

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