TTN and heart disorder: Evidence that these alterations are presumably important in heart disease comes from the following observations: (i) a PKG-dependent titin phosphorylation deficit exists in failing human hearts, along with increased passive stiffness (Krüger et al. 2009; Kötter et al. 2013); (ii) a reduced myocardial cGMP concentration and PKG activity can be found in human and canine diastolic heart failure (van Heerebeek et al. 2012; Hamdani et al. 2013a); and (iii) increased nitrotyrosine levels are detectable in the hearts of diastolic heart failure patients (van Heerebeek et al. 2012).