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Objectives Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. Methods We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. Results This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n  = 390) were 85%, 59% and 42%; for SLE-PAH (n  = 34) they were 97%, 77% and 61%; for MCTD-PAH (n  = 33) they were 97%, 70% and 59%; for UCTD-PAH (n  = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n  = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P  = 0.001). In these patients, the survival estimates were significantly better with initial ERA–PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P  = 0.016 and P  = 0.012, respectively). Conclusions Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA–PDE5i combination therapy compared with initial monotherapy. [ABSTRACT FROM AUTHOR]

Aims Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Methods and results Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Conclusion Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling. [ABSTRACT FROM AUTHOR]

The function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension. While much progress has been made in the treatment of pulmonary hypertension, therapies for the RV are less well established. In this review of treatment strategies for the RV, first we focus on ways to reduce wall stress since this is the main determinant of changes to the ventricle. Secondly, we discuss treatment strategies targeting the detrimental consequences of increased RV wall stress. To reduce wall stress, afterload reduction is the essential. Additionally, preload to the ventricle can be reduced by diuretics, by atrial septostomy, and potentially by mechanical ventricular support. Secondary to ventricular wall stress, left-to-right asynchrony, altered myocardial energy metabolism, and neurohumoral activation will occur. These may be targeted by optimising RV contraction with pacing, by iron supplement, by angiogenesis and improving mitochondrial function, and by neurohumoral modulation, respectively. We conclude that several treatment strategies for the right heart are available; however, evidence is still limited and further research is needed before clinical application can be recommended. [ABSTRACT FROM AUTHOR]

OBJECTIVES Paralysis of the diaphragm is an uncommon condition, which may result in dyspnoea on excertion and in orthopnea. In patients who have symptoms, the paralysed diaphragm is often plicated to prevent its paradoxical movement on inspiration. This procedure brings relief to many patients, but the mechanism for this improvement is not well understood. METHODS Nine symptomatic patients who underwent plication of a unilateral paralysed hemidiaphragm were prospectively evaluated. All patients underwent pulmonary function tests and cardiopulmonary exercise tests before surgery and repeated them after surgery. RESULTS Patients with hemidiaphragm paralysis before surgery were found to have lower tidal volumes at any given ventilation rate during exercise than normal subjects. A clear and consistent change was found in the manner in which patients increased their ventilation during exercise after surgery. All patients showed an increase in tidal volume for a given ventilation rate, which was significant. The plication procedure reduced the respiratory rate for any exercise level in all patients, and this effect was more pronounced during exercise. CONCLUSIONS In patients with hemidiaphragm paralysis who underwent a diaphragm plication exercise, tidal volumes increased and the ventilatory frequency decreased. Despite this improvement, maximal exercise capacity remained unaltered. [ABSTRACT FROM AUTHOR]

Aims In chronic pulmonary hypertension (PH), right ventricular (RV) failure is associated with shortening of the RV free wall (RVFW) beyond pulmonary valve closure, temporarily paralleled by pronounced lengthening of the left ventricular free wall (LVFW). We hypothesized that this early-diastolic LVFW lengthening is caused by altered RVFW myofibre function and may therefore serve as a non-invasive measure of PH-induced RV (dys)function. Methods and results In 22 idiopathic pulmonary arterial hypertension (IPAH) patients, five chronic thrombo-embolic PH (CTEPH) patients, and six healthy subjects, ventricular volumes and circumferential strains were obtained using magnetic resonance imaging. RV ejection fraction (RVEF) and stroke volume index (RVSVI) were smaller in IPAH and CTEPH patients than in normals (RVEF: 32 ± 12 and 23 ± 19 vs. 59 ± 14%, respectively, both P < 0.01; RVSVI: 32 ± 9 and 23 ± 9 vs. 47 ± 6 mL/m2, both P < 0.001). LV early-diastolic strain index (LVEDSI), defined as LVFW strain in the period between LVFW and RVFW peak shortening normalized for total systolic LVFW shortening, was larger in IPAH and CTEPH patients (0.52 ± 0.33 and 0.55 ± 0.40, both P < 0.01) than in normals (−0.03 ± 0.03). LVEDSI correlated negatively with RVEF (R = −0.74, P < 0.0001) and RVSVI (R = −0.69, P < 0.0001). Three multi-scale computer simulations of PH (all with mean pulmonary artery pressure = 55 mmHg) with complete, incomplete, and no structural adaptation of ventricular walls to local myofibre load showed that LVEDSI increased with deficiency of cardiac adaptation to PH (0.01, 0.52, and 0.84, respectively). Conclusion Early-diastolic LV lengthening reflects inadequate structural adaptation of the RVFW to increased myofibre load and is therefore a useful, non-invasive, and easily obtainable predictor of PH-induced RV dysfunction. [ABSTRACT FROM AUTHOR]

Aims To assess the occurrence and prognostic value of acute vasodilator response (AVR) in paediatric vs. adult pulmonary arterial hypertension, and idiopathic/hereditary pulmonary arterial hypertension (iPAH/HPAH) vs. pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) using three different response criteria. Methods and results Ninety-nine PAH patients underwent AVR testing (37 children, 62 adults; 70 iPAH/HPAH, 29 PAH-CHD). Three response criteria from clinical practice were used to define AVR. The number of responders was evaluated separately in subgroups based on age, diagnosis, and presence of a non-restrictive post-tricuspid shunt. Numbers of responders varied importantly using the different criteria but were always higher in iPAH/HPAH, compared with PAH-CHD. The number of responders did not differ between paediatric and adult iPAH/HPAH. No responders were identified in patients with a post-tricuspid shunt. Acute vasodilator response was associated with improved survival using all three criteria. Low baseline mean right atrial pressure (mRAP) was associated with improved survival in adults (P< 0.001). High baseline mean pulmonary arterial pressure (mPAP)/mean systemic arterial pressure (mSAP) and pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) were associated with worse survival, statistically independent from age, diagnosis, and the presence of a post-tricuspid shunt. Conclusion The proportion of patients with AVR highly depends on the used criteria, but did not differ between paediatric and adult iPAH/HPAH. Current response criteria are not suitable for patients with a post-tricuspid shunt. In both children and adults without post-tricuspid shunts, AVR was associated with improved survival independent of the used criteria. Nevertheless, prognostic value in the individual patient was limited. Baseline mRAP showed a good correlation with survival for adult PAH patients, but not for children. High baseline mPAP/mSAP and PVR/SVR was associated with worse prognosis independent from age, diagnosis, or the presence of a post-tricuspid shunt. [ABSTRACT FROM PUBLISHER]