Revealing the Resilient Right: Insights into Mechanisms of Right Heart Adaptation
Authors:   , van Wezenbeek Joanna Carolina Catharina Maria 
Published: November 2023

Part I Sex differences and markers for RV maladaptation in PH
Sex differences are evident in pulmonary arterial hypertension (PAH) and sex hormones are thought to play a role. In Chapter 2, we observed reduced (DHEA-S) plasma levels in both sexes, but testosterone and androstenedione were reduced in female patients only. Importantly, we also identified a negative association between testosterone and RV adaptation. Furthermore, we show that at end-stage disease the female heart is more severely affected than the male heart, as shown by worse hypertrophy and less capillarization. Our longitudinal data shows that females persevere pressure overload for a longer period which results in a worse end-stage RV phenotype.
Natriuretic peptides including Brain Natriuretic peptides (BNP) and Atrial Natriuretic peptide (ANP) are important cardiac biomarkers that regulate cardiovascular homeostasis. In the editorial in Chapter 3 we evaluate new biomarkers to identify RV maladaptation in PH. Furthermore we observed differences in ANP and BNP at gene and protein levels both systemically and locally in the right heart of precapillary PH. In addition, we observed sex differences in release of NT-proBNP in iPSC-CMs that underwent stretch.
In Chapter 4 we studied unloading of the right ventricle after pulmonary endarterectomy (PEA) in chronic thromboembolic pulmonary hypertension (CTEPH) patients. Although RV diastolic stiffness normalized after PEA, RV mass did not. The decrease in cellular hypertrophy was relatively larger than the decrease in matrix volume after PEA, which indicates incomplete regression of diffuse RV interstitial fibrosis. This is further supported by the persistent increase in levels of collagen biomarkers post-PEA, suggesting active collagen turnover.

Summary part II Phenotyping the right atrium in PH
BMP10 is of interest in precapillary PH since the sole source of its production is in the right atrium. We showed increased BMP10 expression and its downstream targets locally in RA tissue of precapillary PH patients. Although systemic levels of BMP10 were higher, BMP10 activity was preserved. We also observed that higher BMP10 activity in precapillary PH is associated with worse RV function, RV maladaptation and RA dysfunction. Interestingly, after pressure unloading of the right heart in CTEPH patients after PEA, we observed a reduction in BMP10 activity.
Both RA pressure and volume are associated with survival in PAH-patients and are part of the current risk assessment of patients. In Chapter 6, we aimed to fully characterize alterations in the right atrium in precapillary PH. For the first time, we were able to assess human RA PV loops. We showed that increased RA volume and pressure was most evident at the end of ventricular systole and during atrial contraction in precapillary PH. In Chapter 6 we observed evident signs of adaptation of the right atrium also at histological level. Lastly in Chapter 7, we compared the response of the right ventricle to a similar extent of afterload in patients with PAH and HFpEF. Despite a similar extent of pressure overload, the response of the right heart in HFpEF-PH and PAH was different.