Geert Kleinnibbelink

RV Strain-Area Loop following Selexipag 8 179 DISCUSSION The aim of the present study was to explore the impact of 17 weeks of Selexipag on the RV strain-area loop in patients with PAH and, subsequently, relate these outcomes to changes in clinical status. The key outcome, at group level, was that treatment with Selexipag did not change any RV strain-area loop characteristics nor did treatment change other measures of RV function or any clinical outcomes. When stratified to clinical responders (change in NYHA class) and non-responders, we found that the responders showed an increase in RV longitudinal strain and uncoupling, whilst the non-responders showed a decrease in RV longitudinal strain and uncoupling. This is the first study exploring the effect of 17 weeks of Selexipag on RV function in patients with PAH. Our exploratory analysis showed that, at group level, 17 weeks of treatment with Selexipag has no impact on characteristics of the RV strain-area loop or other echocardiographic indices for RV function. This is likely related to the heterogeneous effects of Selexipag i.e. it did not induce (sufficient) afterload reduction in all individuals. To support this notion, indirect echocardiographic measures associated with RV afterload (TR Vmax, PAT, RA size) did not change following Selexipag treatment. Although echocardiography shows moderate relation with invasive assessment of RV afterload 13, 14 , we cannot rule out the presence of a small effect size of Selexipag on pulmonary vascular resistance. Nonetheless, the effect size was too small and/or the duration of follow-up too short to induce relevant and significant effect on RV function across the population. To further explore the impact of Selexipag, we categorized patients into responders and non-responders using clinical outcomes. The hypothesis being that Selexipag successfully reduced pulmonary vascular resistance, and hence improved RV function, in clinical responders. Indeed, the reduction of RV systolic pressure (reduced TR Vmax) in the responders demonstrates a decrease in RV afterload. The reduction in RV afterload, subsequently, may explain the increase in peak RV longitudinal strain and greater uncoupling of the RV strain-area loop. Indeed, previous studies have found that reduction in pulmonary vascular resistance is associated with improvement of RV longitudinal strain following treatment. 15 The greater uncoupling (in early and late diastole) of the strain-area loop suggests a decrease in longitudinal contribution to area change in diastole compared

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