Anne-Marie Koop

42 PAB and the development of RVF The tight PAB used in this study led to various degrees of RV failure, in which we made a distinction based on clinical symptoms. About half of the rats developed severe RVF with clinical symptoms that necessitated termination. This would be analogous to NYHA class IV. The other PAB rats did develop RVF (reduced voluntary exercise tolerance, RV dysfunction etc.) but displayed no overt clinical signs. This would be analogous to NYHA class II-III. This variability in phenotype may have different explanations. Firstly, it may represent variability in PAB tightness, as the rats with a tighter PAB would develop a more severe phenotype. However, in figure 1 we showed that systolic RV pressures and PAB gradient were equal in both PAB- and PB+CF groups at both 5 weeks and at the endpoint, which excludes PAB variability as explanation. The fact that the ‘stress’ imposed on all RVs was equal, suggests that the differences in phenotype are explained by differences in adaptation. Indeed, the inherent ability to cope with pressure load appears to differ among rats. As shown in figure 5 , functional parameters are already different between groups at 5 weeks; which is weeks before clinical symptoms occur. This inherent vulnerability for (or resilience against-) RV pressure load is not explained by major differences in genetic make-up as we used an inbred rat strain for all experiments. Rather, our data suggest that differences may exist in the mechanisms regulating diastolic function. Clinical RVF is characterized by diastolic dysfunction with enhanced contractility Recently, there is renewed debate about the involvement of diastolic versus systolic dysfunction in the progression of RV failure. 23 Whereas previously the role of systolic dysfunction has received most attention, the results of the present study stress the importance of diastolic dysfunction in the development of clinical RV failure. These findings are confirmed by recent studies in human ex-plant RV tissue. 24 Surprisingly, no decrease in systolic function, rather increased contractility was observed. Enhanced contractility in RVFmight seemparadoxical, but it is a consistent finding in the chronic pressure overloaded RV 14,16,25,26 and in PAH patients. 24 From previous experimental studies, as well as from a recent study in PAH patients 24 it is known that chronic RV pressure overload induces diastolic dysfunction. 14,16 This study now adds the observation that the occurrence of clinical RVF is associated with deteriorating diastolic function. Diastolic function is the resultant of both active relaxation, which depends on Ca 2+ re-uptake by phospholamban- modulated SERCA2a and sodium-calcium exchanger NCX, and passive chamber properties. Active relaxation of the RV is thought to be disturbed in acute pressure overload. 27 In the current study in chronic pressure load however, active relaxation (tau) was only mildly prolonged and did not further increase with clinical RVF.