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Pulmonary arterial hypertension (PAH) is a progressive and lethal pulmonary vascular disease (PVD). Although in recent years outcome has improved by new treatments that delay disease progression, a cure has not yet been achieved. In PAH associated with congenital heart disease (CHD), remodeling of the pulmonary vasculature reaches an irreversible phenotype similar to all forms of end-stage PAH. In PAH-CHD, however, also an early stage is recognised, which can be completely reversible. This reversible phase has never been recognised in other forms of PAH, most likely because these patients are only diagnosed once advanced disease has developed. We propose that the clinical model of PAH-CHD, with an early reversible and advanced irreversible stage, offers unique opportunities to study pathophysiological and molecular mechanisms that orchestrate the transition from reversible medial hypertrophy into irreversible plexiform lesions. Comprehension of these mechanisms is not only pivotal in clinical assessment of disease progression and operability of patients with PAH-CHD; specific targeting of these mechanisms may also lead to pharmacological interventions that transform ‘irreversible’ plexiform lesions into a reversible PVD: one that is amenable for a cure. In recent years, significant steps have been made in the strive to ‘reverse the irreversible’. This review provides an overview of current clinical and experimental knowledge on the reversibility of PAH, focussing on flow-associated mechanisms, and the near-future potential to advance this field.

Purpose: Treatment of paediatric pulmonary arterial hypertension (PAH) has been evolving from PAH-targeted mono-therapy to add-on combination therapy. However, the effectiveness of add-on PAH-therapy has not yet been scientifically confirmed in paediatric PAH patients. The purpose of this study was to determine the effect of sildenafil add-on therapy in paediatric PAH patients initially treated with endothelin receptor antagonists (ERA). Methods: Follow-up data of 26 consecutive paediatric PAH patients initially treated with ERA mono-therapy at the Dutch national referral centre for paediatric PAH between January 2007 and 2013, were retrospectively reviewed. Patients received add-on sildenafil therapy at clinical worsening or insufficient improvement despite ERA mono-therapy, defined as a rise in WHO-functional class (WHO-FC) or sustained WHO-FC III. Results: Fourteen patients received add-on sildenafil therapy, 12 remained on ERA mono-therapy. Baseline characteristics, 6-minute walk distance (6MWD), WHO-FC, NT-proBNP, and hemodynamic measurements were similar between both patient groups. Patients that received add-on sildenafil therapy had more advanced disease progression during ERA mono-therapy, with higher WHO-FC during follow-up (p=0.042). After addition of sildenafil therapy 6MWD improved significantly at 5, 11 and 21 months of follow-up. In addition, mean WHO-FC improved (3.1 to 2.6 at a mean of 6.7 months follow-up, p=0.020). Despite the more advanced disease progression of these patients before sildenafil add-on, they showed improved survival (p=0.074) compared to patients that remained on ERA mono-therapy. ![Figure][1] Mean (95%-CI) 6-minute walk distance Conclusion: Sildenafil add-on therapy to ERA mono-therapy was effective in paediatric PAH patients, leading to significant improvement of clinical condition and improved survival. [1]: pending:yes

Purpose: We aimed to identify pathways involved in experimental right ventricular failure (RVF) due to chronic pressure overload. Methods: Wistar rats were subjected to pulmonary artery banding (PAB) (1.1mm, n=12) or sham surgery (CON, n=7) and then daily checked for clinical signs of RVF (inactivity, ruffled fur, dyspnea, ascites). At the onset of clinical RVF (necessitating termination) pressure-volume analysis was performed in the rats with RVF and in randomly selected PAB rats without clinical signs of RVF (RVDysfunction, RVD) at the same time points. Gene micro array was performed on RV tissue using GeneChip Rat Gene 1.1 ST (Affymetrics). Quality control and normalization (RMA) were performed according to international standards. False discovery rate was set to 1.3 in RVF vs. RVD. Micro array data were analyzed using gene-set enrichment analysis (GSEA), gene ontology mapping (biological processes) (ErmineJ) and pathway analysis (DAVID). Results: All rats with PAB had RV dysfunction, but clinical RVF ensued in only 5 rats, after a period of 52±5 days. RVF rats had pericardial effusion, liver congestion, and widely dilated right atria, in contrast to RVD rats. RVF rats also had significantly lower cardiac index (0.10±0.04 vs. 0.19±0.04 mL/min/g, RVF vs. RVD, p

Purpose: Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease with a high mortality and to date no curable treatment. Increased pulmonary blood flow, as in congenital heart disease, is an essential trigger for the development of neointimal lesions that are characteristic for PAH. We recently identified a flow-specific signal, Egr-1, which was activated in both experimental and human PAH. The aim of the present study was to identify the role of Egr-1 in the development of neointimal lesions in experimental PAH. Methods: In wistar rats (n=76), flow-associated PAH was created by combining monocrotaline with an aortocaval (av) shunt. Egr-1 was inhibited via chronic intravenous delivery (every 48h) of catalytic oligodeoxynucleotides (called DNAzymes) specifically targeting Egr-1 in vivo via RNA degradation. Starting at av-shunt, rats were randomized for either DNAzyme therapy (PAH\_DZ), scrambled DNAzymes (PAH\_SCR; scrambled oligonucleotides that do not recognize Egr-1 RNA) or vehicle (PAH_VEH). Sham operated rats served as control (Con). Increased flow was confirmed by echocardiography. At both 1 week and 3 weeks after increased flow animals underwent hemodynamic evaluation and were sacrificed for further histopathological analysis. Results: At 3 weeks PAH rats had increased vascular occlusion (33%±3, vs. 2±0%, p