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Vascular actions of NO include direct vasodilation, indirect vasodilation by inhibiting vasoconstrictor influences, along with anti-thrombotic, anti-inflammatory and anti-proliferative effects.79 Low myocardial cyclic guanosine monophosphate (cGMP)-dependent protein kinase type I (PKG) activity is associated with raised cardiomyocyte resting tension and increased myocardial nitrosative/oxidative stress in HFpEF patients compared with HFrEF patients and patients with aortic stenosis.80 In several cohorts, HFpEF patients had lower serum NO-derived metabolites than those of HFrEF patients or controls without HF.81,82 However, this lower serum NO level did not correlate with the degree of LV hypertrophy or myocardial fibrosis by imaging.82 Thus, reduced NO bioavailability is considered to be an integral part of the inflammatory pathogenesis that results in myocardial dysfunction in HFpEF ( Table 2 ).83 In a rat model of T2D, long-term application of the phosphodiesterase-5A inhibitor vardenafil, started in the prediabetic phase, effectively prevented development of HFpEF, reduced the pathophysiological features of T2D-associated cardiomyopathy and restored the activity of the cGMPPKG axis.84 Unfortunately, human clinical trials testing NO as a therapeutic strategy have not demonstrated clinical benefits in HFpEF.8588 Recently, results from a mouse model of HFpEF demonstrated that genetic inhibition of inducible NOS improves ventricular relaxation and exercise performance, providing a biological explanation for the failure of NO-inducing approaches as therapeutic strategies.89 Adrenomedullin Adrenomedullin (ADM) is a potent vasodilator peptide, with additional immunomodulating, antiproliferative and antiapoptotic effects.90 ADM gene expression is significantly increased in the Dahl salt-sensitive rat model of HFpEF.91 In a large community-based study, mid-regional pro-ADM (MR-proADM) could help in identifying new-onset HFpEF.92 In the same way, in HFpEF patients from the KaRen biomarker substudy, ADM predicted HF severity and prognosis.38 In a cross-sectional analysis from the prospective cohort program DIAST-CHF, MR-proADM was independently associated with submaximal exercise capacity when added to the base model, which included classical risk factors for HFpEF.93 In a prospective study, HFpEF patients displayed higher levels of MR-proADM at rest and during exercise in comparison with subjects without HF

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Updates and Progress in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) in the Era of Novel/Targeted Therapies in 2019 and Beyond

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