Constantijn Franssen et al. JCHF 2016;4:312-324 Downstream Effects of Microvascular Inflammation in HFpEF Myocardium Systemic inflammation induces inflammatory activation of the endothelium of myocardial microcirculation. This leads to enhanced endothelial expression of adhesion molecules such as ICAM-1, VCAM, and E-selectin. Because of inflammatory activation, NOX2 is upregulated in endothelial cells. This results in oxidative stress, increased levels of H2O2, uncoupling of eNOS, decreased NO bioavailability, and formation of 3-nitrotyrosine. In cardiomyocytes, decreased NO bioavailability leads to less stimulation of sGC, reduced formation of cGMP, and diminished PKG activity. Lack of PKG activity is associated with decreased titin phosphorylation and increased passive stiffness of cardiomyocytes. cGMP can also be generated by NPs which activate pGC. Because of the low cGMP concentration, the latter pathway failed to compensate for the decreased NO-bioavailability. cGMP = cyclic guanosine monophosphate; eNOS = endothelial nitric oxide synthase; H2O2 = hydrogen peroxide; ICAM-1 = intercellular adhesion molecule-1; NO = nitric oxide; NOX2 = NADPH nicotinamide adenine dinucleotide phosphate oxidase 2; NPs = natriuretic peptides; pGC = particulate guanylate cyclase; PKG = protein kinase G; sGC = soluble guanylate cyclase; VCAM = vascular cell adhesion molecule. Constantijn Franssen et al. JCHF 2016;4:312-324 American College of Cardiology Foundation