1. Eur Respir Rev. 2018 Apr 13;27(148). pii: 180004. doi: 10.1183/16000617.0004-2018. Print 2018 Jun 30. Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era. Savale L(1)(2)(3), Guignabert C(1)(3), Weatherald J(4)(5), Humbert M(1)(2)(3). Pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) include different cardiopulmonary disorders in which the interaction of multiple genes with environmental and behavioural factors modulates the onset and the progression of these severe conditions. Although the development of therapeutic agents that modulate abnormalities in three major pathobiological pathways for PAH has revolutionised our approach to the treatment of PAH, the long-term survival rate remains unsatisfactory. Accumulating evidence has underlined that clinical outcomes and responses to therapy in PAH are modified by multiple factors, including genetic variations, which will be different for each individual. Since precision medicine, also known as stratified medicine or personalised medicine, aims to better target intervention to the individual while maximising benefit and minimising harm, it has significant potential advantages. This article aims to assemble and discuss the different initiatives that are currently underway in the PH/PAH fields together with the opportunities and prospects for their use in the near future. 2. J Heart Lung Transplant. 2018 Mar 17. pii: S1053-2498(18)31395-0. doi:10.1016/j.healun.2018.03.010. [Epub ahead of print] Use of supplemental oxygen in patients with pulmonary arterial hypertension in REVEAL. Farber HW(1), Badesch DB(2), Benza RL(3), Elliott CG(4), Frantz RP(5), McGoon MD(5), Selej M(6), Zhao C(6), Frost AE(7). BACKGROUND: Supplemental low-flow oxygen is recommended by treatment guidelines as supportive therapy for patients with pulmonary arterial hypertension (PAH), based largely on expert opinion. Reduced diffusing capacity of lung carbon monoxide (DLCO) is associated with increased mortality in PAH. Reduced DLCO is also associated with relative hypoxemia, making the effects of supplemental oxygen use of particular interest in this sub-population. METHODS: Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by presence or absence of supplemental oxygen use and by degree of DLCO reduction. Kaplan-Meier survival estimates were calculated by group. RESULTS: Of 3,046 patients, 57% used supplemental oxygen and 43% did not. Supplemental oxygen users had worse prognostic factors and more PAH-specific medication use. Of the 424 patients with severe DLCO reduction (<40% of predicted), 76% used oxygen and 24% did not. Patients with severe DLCO reduction who used supplemental oxygen had a significantly lower risk of all-cause mortality than those who did
not (hazard ratio 0.56; 95% confidence interval 0.39 to 0.83; p = 0.0033). This was true for newly diagnosed and previously diagnosed patients. There was no relationship between oxygen use and outcomes in patients with no, mild, or moderate DLCO reduction. CONCLUSIONS: In this observational study, the risk of death was significantly lower for patients with severe DLCO reduction who received supplemental oxygen compared with those who did not. A randomized trial is warranted to further investigate the relationship between supplemental oxygen use and outcomes in PAH. 3. Respiration. 2018 Apr 11. doi: 10.1159/000488000. [Epub ahead of print] Risk Factor Profiles Achieved with Medical Therapy in Prevalent Patients with Pulmonary Arterial and Distal Chronic Thromboembolic Pulmonary Hypertension. Bartenstein P, Saxer S, Appenzeller P, Lichtblau M, Schwarz EI, Ulrich S. BACKGROUND: The latest pulmonary hypertension (PH) guidelines define therapeutic goals in terms of symptoms, exercise capacity, and haemodynamics for patients with pulmonary arterial hypertension (PAH) and recommend advanced combined medical therapy. For inoperable or post-surgical residual distal chronic thromboembolic PH (CTEPH) medical treatment is similarly advised. OBJECTIVES: We analysed whether risk factor goals are achieved and combination therapy is used in prevalent patients with PAH or distal CTEPH. METHODS: PAH or distal CTEPH patients who were seen at the University Hospital Zurich during the last year were analysed in terms of demography, clinical data, medication, and therapeutic goals. Achievement of therapeutic goals was defined as New York Heart Association (NYHA) class II, N-terminal pro-brain natriuretic peptide (NTpro-BNP) < 300 ng/l, and 6-min walking distance (6MWD) > 440 m. RESULTS: A total of 108 PAH patients (age 59 ± 18 years, 62% female, 64% idiopathic, 36% associated) and 38 distal CTEPH patients (age 69 ± 14 years, 55% female) were included. They had been diagnosed on average 66 ± 48 months (±SD) previously. The percentage of PAH/CTEPH patients with NYHA II was 52/53, respectfully, the percentage of those with NTproBNP < 300 ng/l was 61/52, and with 6MWD > 440 m 63/50. Overall, 33/31% fulfilled 3 and 29/35% fulfilled 2 of these goals. Regarding therapy, 43% of PAH patients were on double and 10% on triple combination therapy, whereas 16% of distal CTEPH patients were on double and 3% on triple combination therapy. CONCLUSIONS: In this real-life cohort of prevalent patients with PAH or distal CTEPH, targeted drug therapy resulted in an achievement of 2/3 predefined therapeutic goals in 2/3 of patients. Patients with PAH were more likely to receive combination therapy compared to CTEPH patients.
4. PLoS One. 2018 Mar 28;13(3):e0193226. doi: 10.1371/journal.pone.0193226.eCollection 2018. Association between six-minute walk distance and long-term outcomes in patients with pulmonary arterial hypertension: Data from the randomized SERAPHIN trial. Souza R(1), Channick RN(2), Delcroix M(3), Galiè N(4), Ghofrani HA(5)(6), Jansa P(7), Le Brun FO(8), Mehta S(9), Perchenet L(10), Pulido T(11), Sastry BKS(12), Sitbon O(13)(14)(15), Torbicki A(16), Rubin LJ(17), Simonneau G(13). BACKGROUND: Patients with pulmonary arterial hypertension who achieve a six-minute walk distance of 380-440 m may have improved prognosis. Using the randomized controlled trial of macitentan in pulmonary arterial hypertension (SERAPHIN), the association between six-minute walk distance and long-term outcomes was explored. METHODS: Patients with six-minute walk distance data at Month 6 were dichotomized as above or below the median six-minute walk distance (400 m) and assessed for future risk of pulmonary arterial hypertension-related death or hospitalization and all-cause death. Additionally, six-minute walk distance values at baseline, Month 6 and the change from baseline to Month 6 were categorized by quartiles. All associations were analyzed by the Kaplan-Meier method using a log-rank test and Cox regression models. RESULTS: Patients with a six-minute walk distance >400 m vs. 400 m at Month 6 have a reduced risk of pulmonary arterial hypertensionrelated death or hospitalization (hazard ratio 0.48; 95% confidence interval 0.33-0.69). The risk was also lower for patients with higher quartiles of six-minute walk distance at baseline or Month 6 (baseline: hazard ratio [Q4 (>430 m) vs. Q1 ( 300 m)] 0.23; 95% confidence interval 0.15-0.36; Month 6: hazard ratio [Q4 (>455 m) vs. Q1 ( 348 m)] 0.33; 95% confidence interval 0.19-0.55). In contrast, six-minute walk distance changes at Month 6 were not associated with the risk of pulmonary arterial hypertension-related death or hospitalization (p = 0.477). These findings were consistent when adjusted for known confounders. Similar results were observed for the risk of all-cause death up to end of study. CONCLUSIONS: Patients with pulmonary arterial hypertension walking >400 m had better long-term prognosis. Although changes in six-minute walk distance were not associated with long-term outcomes, assessing absolute six-minute walk distance values remains important in the clinical management of patients with pulmonary arterial hypertension. 5. Int J Cardiol. 2018 Mar 7. pii: S0167-5273(17)37889-0. doi: 10.1016/j.ijcard.2018.03.020. [Epub ahead of print] Fluid challenge predicts clinical worsening in pulmonary arterial hypertension. D'Alto M(1), Motoji Y(2), Romeo E(3), Argiento P(3), Di Marco GM(3), Mattera Iacono A(3), D'Andrea A(3), Rea G(4), Golino P(3), Naeije R(2). AIM: A fluid challenge with rapid saline infusion during right heart
catheterization has been shown to be useful for the differential diagnosis between pre- and post-capillary pulmonary hypertension. The aim of this study was to evaluate the prognostic relevance of fluid challenge-induced changes in pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH). METHODS: Overall, 118 PAH patients (mean age 57 ± 15 years, 80 female) underwent hemodynamic measurements before and after rapid saline infusion (7 ml/kg in 10 min) and were followed up for 19 ± 4 months. RESULTS: Thirty-two patients (27%) had a clinical worsening event defined as the occurrence of one of the following: death, lung transplantation, initiation of parenteral prostanoids, or worsening of PAH (defined as the presence of all of the three following components: a decrease in the 6-minute walk distance of at least 15% from baseline, worsening of PAH symptoms, and need for new PAH treatment). Cardiac index (CI), stroke volume and pulmonary artery compliance were lower whereas right atrial pressure (RAP), the ratio of RAP to pulmonary artery wedge pressure (PAWP) and pulmonary vascular resistance were higher in patients with a clinical worsening event versus patients without events, both at baseline and after fluid challenge (all p < 0.01). At multivariable Cox proportional hazards regression analysis, a post-fluid challenge CI <2.8 L/min/m2 (hazard ratio 0.0143; 95% confidence interval 0.006-0.3383; p = 0.009) was the only independent predictor of outcome. CONCLUSIONS: CI measured after a fluid challenge is an independent predictor of outcome in PAH. 6. Eur Respir J. 2018 Feb 7;51(2). pii: 1701886. doi: 10.1183/13993003.01886-2017. Print 2018 Feb. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Vachiéry JL(1), Delcroix M(2), Al-Hiti H(3), Efficace M(4), Hutyra M(5), Lack G(6), Papadakis K(7), Rubin LJ(8). The MELODY-1 study evaluated macitentan for pulmonary hypertension because of left heart disease (PH-LHD) in patients with combined post- and pre-capillary PH.63 patients with PH-LHD and diastolic pressure gradient 7 mmhg and pulmonary vascular resistance (PVR) >3WU were randomised to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The main end-point assessed a composite of significant fluid retention (weight gain 5% or 5 kg because of fluid overload or parenteral diuretic administration) or worsening in New York Heart Association functional class from baseline to end of treatment. Exploratory end-points included changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and haemodynamics at week 12.Seven macitentan-treated and four placebo-treated
patients experienced significant fluid retention/worsening functional class; treatment difference, 10.08% (95% CI -15.07-33.26; p=0.34). The difference, driven by the fluid retention component, was apparent within the first month. At week 12, versus placebo, the macitentan group showed no change in PVR, mean right atrial pressure or pulmonary arterial wedge pressure; a non-significant increase in cardiac index (treatment effect 0.4 (95% CI 0.1-0.7) L min-1 m-2) and decrease in NT-proBNP (0.77 (0.55-1.08)) was observed. Adverse events and serious adverse events were numerically more frequent with macitentan versus placebo.macitentan-treated patients were quantitatively more likely to experience significant fluid retention versus placebo. Macitentan resulted in no significant changes in any exploratory end-points. 7. Respir Med. 2018 Jan;134:42-46. doi: 10.1016/j.rmed.2017.11.020. Epub 2017 Dec 2. Pulmonary arterial hypertension in the setting of scleroderma is different than in the setting of lupus: A review. Bazan IS(1), Mensah KA(2), Rudkovskaia AA(3), Adonteng-Boateng PK(4), Herzog EL(1), Buckley L(2), Fares WH(5). Pulmonary hypertension (PH) is a clinical syndrome that is subdivided into five groups per the World Health Organization (WHO) classification, based largely on hemodynamic and pathophysiologic criteria. WHO Group 1 PH, termed pulmonary arterial hypertension (PAH), is a clinically progressive disease that can eventually lead to right heart failure and death, and it is hemodynamically characterized by pre-capillary PH and increased pulmonary vascular resistance in the absence of elevated left ventricular filling pressures. PAH can be idiopathic, heritable, or associated with a variety of conditions. Connective tissue diseases make up the largest portion of these associated conditions, most commonly systemic sclerosis (SSc), followed by mixed connective tissue disease and systemic lupus erythematous. These etiologies (namely SSc and Lupus) have been grouped together as connective tissue disease-associated PAH, however
emerging evidence suggests they differ in pathogenesis, clinical course, prognosis, and treatment response. This review highlights the differences between SSc-PAH and Lupus-PAH. After introducing the diagnosis, screening, and pathobiology of PAH, we discuss connective tissue disease-associated PAH as a group, and then explore SSc-PAH and SLE-PAH separately, comparing these 2 PAH etiologies.