Is the effect of cGMP modulation by phosphodiesterase‐5 inhibition dependent on the magnitude of pressure overload in the hypertrophic right heart?

We appreciate the review by Jannsen and co-workers regarding ‘The role of cGMP in the physiological and molecular responses of the right ventricle to pressure overload’ (Janssen et al. 2013). The authors raise some important questions related to the ambiguous effects of cGMP modulation in right ventricular hypertrophy and failure caused by pulmonary artery banding. In our view, recently published papers not cited in the review might contribute to answering some of the questions raised in the paper. The authors speculate whether the magnitude of right ventricular pressure overload might influence the response to cGMP modulation by phosphodiesterase-5 (PDE5) inhibition and whether this effect is dependent on high-pressure overloads as in the left ventricle. Four papers have been published on this subject, using rats with surgically implanted bands of different strengths, ranging from 0.5 to 1.7 mm (Andersen et al. 2008, 2013a; Schäfer et al. 2009; Borgdorff et al. 2012). The differences in the degree of banding demonstrate a dose-dependent increase in right ventricular hypertrophy and dysfunction from a state of compensated right ventricular hypertrophy to right ventricular hypertrophy associated with severe failure as evaluated by extracardiac manifestations. There was no antihypertrophic effect of PDE5 inhibition in any of the models. Furthermore, there was no effect of PDE5 inhibition on cGMP activity in the most severe models of pulmonary artery banding. An effect on cGMP was observed only by combining PDE5 inhibition with the soluble guanylate cyclase stimulator BAY 41-2272, but the increase in cGMP was subtle. In a recent paper, cGMP was only increased in right ventricular hypertrophy with failure, but not in compensated right ventricular hypertrophy (Andersen et al. 2013b). In that paper, we investigated the effects of ischaemic preconditioning in the right ventricle subjected to different chronic pressure overloads and found that it was not possible to obtain additional cardioprotection by ischaemic preconditioning when the right ventricle was in a failing state. We speculate that cGMP might already be maximally or near maximally stimulated in the failing right ventricle, preventing further upregulation of the cardioprotective nitric oxide–cGMP– protein kinase G pathway by ischaemic preconditioning. The recent literature suggests that PDE5 inhibition does not exert antihypertrophic effects in the right ventricle of rats even with high-pressure overloads. Whether the pressure-overloaded and failing right ventricle has a highly endogenously stimulated nitric oxide–cGMP–protein kinase G pathway, making further pharmacological stimulation of this system ineffective, is a crucial question that should be addressed in future research. Furthermore, it is still not clear if and how cGMP is regulated differently between the right ventricle and left ventricle as a response to pressure overload. An important note, also mentioned by Janssen et al. (2013), which should be emphasized, is that most of the studies in the right ventricle are performed in rats, whereas most of the studies in the left ventricle are in mice; therefore, the observed differences might be caused by the use of different species and not by right versus left ventricular differences in nitric oxide–cGMP–protein kinase G handling.