Introduction ... Aims. Methods and results

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1 European Journal of Heart Failure (2017) doi: /ejhf.860 Pulmonary hypertension due to left heart disease: analysis of survival according to the haemodynamic classification of the 2015 ESC/ERS guidelines and insights for future changes Massimiliano Palazzini, Fabio Dardi, Alessandra Manes, Maria L. Bacchi Reggiani, Enrico Gotti, Andrea Rinaldi, Alessandra Albini, Enrico Monti, and Nazzareno Galiè* Department of Investigational, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy Received 3 February 2017; revised 24 March 2017; accepted 27 March 2017 Aims Pulmonary hypertension (PH) is a relevant complication of left heart disease (LHD). The 2015 ESC/ERS PH guidelines report two different haemodynamic subsets of PH due to LHD (PH-LHD) based on levels of pulmonary vascular resistance (PVR) and diastolic pressure gradient (DPG): isolated post-capillary PH (Ipc-PH) and combined post- and pre-capillary PH (Cpc-PH). The objective of this study is to evaluate the prognostic value of Ipc-PH and Cpc-PH.... Methods and results Data from 276 consecutive incident patients with PH-LHD were included. According to the guidelines, Ipc-PH is defined by DPG <7 mmhg and/or PVR 3 Wood units (WU) and Cpc-PH by DPG 7 mmhg and/or PVR >3 WU. Using this definition, we identified three patient groups: Ipc-PH with both normal PVR and DPG (108 patients); Cpc-PH with both increased PVR and DPG (66 patients); and an intermediate group with either increased PVR or DPG (102 patients). Survival was estimated using the Kaplan Meier method and compared between groups using the log-rank test. Patients with Ipc-PH had better survival compared with the group of patients with Cpc-PH (P = 0.026) and the intermediate group (P = 0.025). No survival difference was detected between patients with Cpc-PH and the intermediate group (P = 0.891). Patients with normal PVR had a better survival compared with those with elevated PVR (P = 0.012); while no difference was observed according to the level of DPG (P = 0.253).... Conclusion Patients with Ipc-PH have a better prognosis compared with patients with Cpc-PH and with patients with isolated increase of PVR or DPG. Pulmonary vascular resistance has a better predictive value than DPG in patients with PH-LHD.... Keywords Pulmonary hypertension Left heart disease Pulmonary vascular resistance Diastolic pressure gradient Heart failure Introduction Pulmonary hypertension (PH), defined as a mean pulmonary arterial pressure (PAP) 25 mmhg, is a well-recognized complication... of left heart disease (LHD). Pulmonary hypertension due to LHD (PH-LHD) is typically characterized by an increase in pulmonary artery wedge pressure (PAWP) >15 mmhg, which is considered a surrogate for left atrial pressure. 1,2 Two different subsets of *Corresponding author. Department of Investigational, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 9, Bologna, Italy. Tel: , Fax: , nazzareno.galie@unibo.it These authors contributed equally to the study.

2 2 M. Palazzini et al. PH-LHD have been recognized from the pathological, pathophysiological, and haemodynamic points of view: 1 4 the first, defined isolated post-capillary PH (Ipc-PH) is characterized by the pure backward transmission of the increased left atrial pressure through the pulmonary veins and capillaries up to the pulmonary arteries. The second form, called combined post- and pre-capillary PH (Cpc-PH), includes a specific distal pulmonary artery disease, which contributes to further increase in PAP as an addition to the passive component. 1 3 In the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) PH guidelines, an updated haemodynamic definition of the two PH-LHD haemodynamic forms was proposed: 1,2 Ipc-PH was defined by a diastolic pressure gradient (DPG) <7 mmhg and/or pulmonary vascular resistance (PVR) 3 Wood units (WU); Cpc-PH was defined by a DPG 7 mmhg and/or PVR >3 WU. Interestingly, the definitions include patients with isolated increases of DPG 7 mmhg or of PVR >3 WU in both groups, affirming the uncertainties in the proper classification of these patients. In a recent paper, it was proposed to include these unclassifiable cases with isolated increases of DPG or of PVR in the Ipc-PH group, based on the retrospective analysis of a series of patients with PH-LHD. 5 This proposal has sparked an intense scientific debate in this field, which outlines the heterogeneity and ambiguity of the data in the literature. 6,7 The primary objective of the present study was to analyse the prognostic value of PVR and DPG alone or in combination in a population of incident patients with PH-LHD referred to an expert centre for the diagnosis and treatment of PH. The analysis is focused on the 2015 ESC/ERS PH guidelines classification and on the group of patients with an isolated elevation of PVR or DPG, which cannot be properly classified based on the present definitions of Ipc-PH and Cpc-PH. The secondary objective of the study will be the assessment of the prognostic value of all four parameters of interest which have been proposed as candidates for the haemodynamic classification of PH-LHD: DPG, pulmonary artery compliance (PAC), PVR, and transpulmonary pressure gradient (TPG). 1 3,8 Methods Study design and patient population Data from all consecutive patients with PH referred to the Pulmonary Vascular Disease Centre of the Bologna University Hospital are included in a prospective electronic registry (ARCA) approved by the institutional ethics committee. Patients provided consent before entering the registry. At baseline, all patients underwent, according to the PH guidelines, 1,2,9 an extensive work-up including the following assessments: clinical evaluation, World Health Organization functional class estimate, 6 min walk test, electrocardiogram, echocardiogram, ventilation perfusion lung scan, arterial blood gases, chest multi-detector computed tomography and lung function tests (including carbon monoxide diffusion capacity measurement), complete biological laboratory evaluation including immunological work-up, and right heart catheterization. The current retrospective analysis of the prospective ARCA registry included consecutive incident patients with PH-LHD referred between June 1997 and June Patients were considered incident if the first... right heart catheterization confirming the diagnosis of PH-LHD was performed in our centre. In accordance with the ESC/ERS PH guidelines, the diagnosis of PH-LHD was based on mean PAP 25 mmhg, PAWP >15 mmhg, and the concurrent presence of LHD. 1,2 Three aetiological subgroups of patients with PH-LHD were identified: heart failure with reduced left ventricular ejection fraction (HFrEF) if left ventricular ejection fraction (LVEF) was 45%, HF with preserved ejection fraction (HFpEF) if LVEF was >45%, and valvular heart diseases (VHD) in the case of moderate to severe mitral and/or aortic native valve disease or valve prosthesis. Echocardiographic measurements were performed according to standard methods. The patients were followed until death or the end of the study period (June 2015) and were treated according to the contemporary guidelines, 1,2,9,10 receiving optimal medical and, when indicated, interventional or surgical treatment for the underlying LHD. Right heart catheterization Patients underwent right heart catheterization with a balloon-tipped, flow-directed catheter, placed through the right internal jugular vein to the pulmonary artery and following a pre-specified protocol. Haemodynamics were measured at baseline after optimizing the diuretic treatment, and the heart rate control in the case of atrial fibrillation. Cardiac index was determined as the mean of three (if sinus rhythm) to five (if atrial fibrillation/flutter) separate measurements using the thermodilution method. Systemic arterial pressure was measured non-invasively. Mean right atrial pressure (RAP), systolic/diastolic/mean pulmonary artery pressure (s/d/m PAP), and PAWP were recorded at end-expiration. TPG was assessed as the difference between mpap and PAWP. PVR was calculated in WU as TPG divided by cardiac output. DPG was calculated as the difference between dpap and PAWP. PAC was calculated as stroke volume in millilitres divided by the difference between spap and dpap. Stroke volume was assessed as the cardiac output in millilitres per minute divided by the heart rate. Post-capillary PH was defined as mpap 25 mmhg and PAWP >15 mmhg. In accordance with the 2015 ESC/ERS PH guidelines, 1,2 Ipc-PH was defined as DPG <7 mmhg and PVR 3 WU, and Cpc-PH was defined as DPG 7 mmhg and PVR >3 WU. Patients with an isolated increase of DPG 7 mmhg or PVR >3 WU, which can be classified as either Ipc-PH or Cpc-PH, 1,2 were considered as a third intermediate group. Endpoints The primary endpoint was all-cause death. Statistical analysis Categorical variables were expressed as number and percentage, and compared using the χ 2 test. Continuous variables were expressed as median and interquartile range, and compared using the Kruskal Wallis test. For the primary endpoint, survival was estimated using the Kaplan Meier method and compared using the log-rank test. Cox analysis was performed to assess the univariate risk of all-cause mortality for DPG, PAC, PVR, and TPG. The four parameters were utilized both as continuous variables or binary variables according with limits reported in the literature. 1 3,8 As these four parameters are variably correlated with one another because of the concurrent inclusion of the same pulmonary arterial pressures and flows even if in different forms, we did not perform a multivariable analysis. A P-value

3 Pulmonary hypertension due to left heart disease 3 Table 1 Clinical, demographic, functional, exercise, and haemodynamic characteristics of 276 patients with pulmonary hypertension due to left heart disease, stratified according to the three subgroups of patients identified by the 2015 ESC/ERS guidelines haemodynamic classification All Ipc-PH with normal PVR and DPG a Intermediate group with increased PVR or DPG b Cpc-PH with increased PVR and DPG c P-value d (n = 276) (n = 108) (n = 102) (n = 66)... Aetiology (%) HFrEF/HFpEF/VHD 9/41/50 8/45/47 9/39/52 9/38/ Age (years) 69 (60 75) 68 (60 73) * 72 (63 78) * 67 (56 73) Male sex (%) WHO-FC III IV (%) * 66 * 77 < MWT (m) 340 ( ) 381 ( ) 332 ( ) 300 ( ) (n = 178) (n = 70) (n = 62) (n = 46) HR (b.p.m.) 75 (65 85) 71 (64 85) 71 (63 81) 80 (68 85) RAP (mmhg) 12 (8 16) 10 (8 15) 11 (9 15) 14(11 18) <0.001 spap (mmhg) 60 (48 76) 47 (42 55) * 67 (55 78) * 81 (64 97) <0.001 dpap (mmhg) 22 (18 29) 18 (16 21) * 22 (19 27) * 33 (29 38) <0.001 mpap (mmhg) 37 (31 46) 30 (27 35) * 40 (34 46) * 52 (42 60) <0.001 PAWP (mmhg) 20 (18 23) 20 (17 24) 20 (17 22) 20 (17 23) DPG (mmhg) 1 ( 2 to7) 1 ( 3 to1) * 1 ( 1 to 3) * 12(9 15) <0.001 TPG (mmhg) 16 (12 24) 11 (9 14) * 18(15 22) * 31 (24 36) <0.001 CI (L/min/m 2 ) 2.6 ( ) 2.9 ( ) * 2.4 ( ) * 2.4 ( ) <0.001 PVR (WU) 3.6 ( ) 2.2 ( ) * 4.1 ( ) * 6.5 ( ) <0.001 SVR (WU) 17.4 ( ) 15.4 ( ) * 19.3 ( ) * 17.4 ( ) <0.001 PAC (ml/mmhg) 1.76 ( ) 2.32 ( ) * 1.46 ( ) * 1.33 ( ) <0.001 PA O 2 Sat (%) 65 (58 70) 68 (63 72) * 63 (57 68) * 60 (54 66) <0.001 LVEDVI (ml/m 2 ) 48 (40 59) 49 (42 60) 49 (42 60) 44 (32 51) LVEF (%) 62 (56 68) 63 (56 69) 63 (58 68) 62 (52 67) Values are expressed as median (25th to 75th percentile) unless otherwise specified. a PVR 3 WUandDPG<7mmHg. b PVR >3 WUorDPG 7mmHg. c PVR >3 WUandDPG 7mmHg. d Comparison between the three subgroups. * Statistically significant difference (P-value <0.05) between Ipc-PH with normal PVR and DPG and Intermediate group with increased PVR or DPG; statistically significant difference (P-value <0.05) between Intermediate group with increased PVR or DPG and Cpc-PH with increased PVR and DPG; statistically significant difference (P-value <0.05) between Ipc-PH with normal PVR and DPG and Cpc-PH with increased PVR and DPG. 6MWT, 6 min walk test; CI, cardiac index; Cpc-PH, combined post- and pre-capillary PH with elevated PVR and DPG; dpap, diastolic pulmonary artery pressure; DPG, diastolic pressure gradient; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; Ipc-PH, isolated post-capillary PH with normal PVR and DPG; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; mpap, mean pulmonary arterial pressure; PAC, pulmonary arterial compliance [stroke volume/(spap dpap)]; PA O 2 Sat, pulmonary arterial oxygen saturation; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; spap, systolic pulmonary artery pressure; SVR, systemic vascular resistance; TPG, transpulmonary pressure gradient (mpap PAWP); VHD, valvular heart disease; WHO-FC, World Health Organization functional class. (two-tailed) of <0.05 was considered significant. Statistical analyses were performed using STATA/SE 12.0 (StataCorp LP, College Station, TX, USA). Results In total, 276 incident patients with PH-LHD were enrolled during the study period. Clinical, functional, and haemodynamic baseline characteristics of the whole group and of the three subgroups of patients identified using the 2015 ESC/ERS haemodynamic classification (Ipc-PH with combined normal DPG and PVR, isolated increase of DPG or PVR, and Cpc-PH with combined increase of DPG and PVR) are shown in Table 1. In the overall population, 50% of patients had VHD, 41% had HFpEF, and 9% had HFrEF: this distribution was similar in the three... haemodynamic subgroups (Table 1), including the type of VHD. Patients with an isolated increase of PVR or DPG had intermediate functional capacity and haemodynamic profile compared with patients with Ipc-PH with normal DPG and PVR, and patients with Cpc-PH with combined increased DPG and PVR. The stratification of the patients according to DPG and PVR values is reported in Table 2. Almost all patients with DPG 7 mmhg also had PVR >3 WU, while 40% of patients with PVR >3WUalso had a DPG 7 mmhg. Patients with isolated increase of PVR (n=97, 35.1%) and isolated increase of DPG (n=5, 1.8%) had similar survival (Figure 1) even if the reduced size of the latter group does not allow a full-powered analysis. The survival of patients with Ipc-PH and normal PVR and DPG, isolated increase of PVR or DPG, and Cpc-PH with elevated PVR

4 4 M. Palazzini et al. Table 2 Patients with pulmonary hypertension due to left heart disease stratified according to pulmonary vascular resistance and diastolic pressure gradient PVR 3 WU PVR>3 WU... DPG <7 mmhg 108 (39.2%) 97 (35.1%) DPG 7 mmhg 5 (1.8%) 66 (23.9%) χ 2 P < DPG, diastolic pressure gradient; PVR, pulmonary vascular resistance. and DPG is shown in Figure 2. Patients with Ipc-PH and normal PVR and DPG had a better survival compared with the other two subgroups. The survival of patients with either PVR or DPG as single parameters (normal vs. increased), irrespective of the value of the other, is shown in Figure 3. Patients with normal PVR had a better survival compared with those with elevated PVR, while no difference was observed with the level of DPG. There was no significant difference in survival according to the underlying aetiology (Figure 4). The univariate risks of all-cause mortality for DPG, PAC, PVR, and TPG are reported in Table 3. The correlation between PVR and PAC is reported in Figure 5. Discussion The results of this study suggest that an isolated increase of PVR or DPG in patients portends a worse prognosis compared with patients with Ipc-PH and both normal parameters. The survival of patients with an isolated increase of PVR or DPG is similar to that of patients with Cpc-PH and concurrent elevation of both... parameters. Based on these data, patients with PH-LHD and a single increase of PVR or DPG should be included in the Cpc-PH group. 1,2 Interestingly, the functional capacity and the haemodynamic profile of patients with a single increase of PVR or DPG are intermediate compared with patients with Ipc-PH with combined normal DPG and PVR and Cpc-PH with combined increased parameters (Table 1). This may suggest that the group with a single increase of PVR or DPG may represent an intermediate stage from Ipc-PH to fully developed Cpc-PH. In any case, further studies are needed to confirm this hypothesis. In our series of 276 patients (Tables 1 and 2), most cases with a single increase of PVR or DPG (36.9%) were patients with isolated elevation of PVR (35.1%) rather than isolated elevation of DPG (1.8%). Moreover, when we assessed survival of the entire population according to PVR or DPG as distinct parameters (Figure 3), only the former was predictive. Therefore, the predominant prognostic value of PVR compared with DPG in our series may explain the similar prognosis of patients with isolated elevation of PVR or DPG and subjects with Cpc-PH and both parameters increased. The available data on the prognostic value of these two parameters in patients with PH-LHD are heterogeneous, with different studies identifying either DPG, PVR, 8,14 or both 15 as predictors of mortality. Multiple factors may explain these different results, including the retrospective nature of all studies and the heterogeneity of the aetiology of the patient populations. In fact, three studies included almost exclusively patients with HFrEF, 8,14,16 three studies included a large number of patients with HFpEF ranging from 30 to 70% of the population, 11,13,15 and three studies included either in part 11,13 or exclusively 12 patients with VHD. In addition, in two studies, the prognosis was assessed either after heart transplantation 16 or after percutaneous transcatheter aortic valve implantation. 12 Figure 1 Survival of 102 patients with pulmonary hypertension due to left heart disease and isolated increase of pulmonary vascular resistance (PVR) or isolated increase of diastolic pressure gradient (DPG). WU, Wood units.

5 Pulmonary hypertension due to left heart disease 5 Figure 2 Survival of 276 patients with pulmonary hypertension (PH) due to left heart disease and isolated pre-capillary pulmonary hypertension (Ipc-PH) with normal pulmonary vascular resistance and diastolic pressure gradient, combined pre- and post-capillary pulmonary hypertension (Cpc-PH) with elevated pulmonary vascular resistance and diastolic pressure gradient, and an intermediate group with isolated increase of pulmonary vascular resistance or diastolic pressure gradient (Intermediate). Overall log-rank test, P = 0.044; Ipc-PH vs. Intermediate, P = 0.025; Ipc-PH vs. Cpc-PH, P = 0.026; CpcPH vs. Intermediate, P = Figure 3 Survival of 276 patients with pulmonary hypertension due to left heart disease according to pulmonary vascular resistance (PVR; A) or diastolic pressure gradient (DPG; B) values. WU, Wood units. In our analysis, the aetiology of PH-LHD was predominantly VHD (50%) and HFpEF (41%) with a rather small group of subjects with HFrEF (9%). Interestingly, when we assessed the survival of the three aetiology subgroups (Figure 4), we could not find a significant difference. This suggests that in the presence of PH, the underlying LHD may not consistently influence the prognosis. In any case, the sample size of our study does not allow us to clarify whether the predictive value of PVR or DPG (or other parameters of interest) may vary according to the different aetiologies of PH-LHD.... According to the results of our study, we could suggest amending the ESC/ERS PH guidelines definition of Ipc-PH as the concomitant presence of normal PVR and DPG. In this case, Cpc-PH would include both patients with isolated or combined increase of PVR and DPG. This is in contrast with an opposite proposal by Gerges et al. 5,11 Various reasons may explain this discrepancy, including diverse selection criteria, referral patterns, and aetiology of the patient populations, and different treatment approaches and follow-up strategies. In our study we included only incident

6 6 M. Palazzini et al. Figure 4 Survival of 276 patients with pulmonary hypertension due to left heart disease according to the aetiology. Overall log-rank test P = HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; VHD, valvular heart disease. Table 3 Univariate Cox analysis for survival according to continuous or binary parameters in 276 patients with pulmonary hypertension due to left heart disease Hazard ratio P-value (95% confidence interval)... DPG (mmhg), continuous ( ) DPG 7 mmhg, binary ( ) TPG (mmhg), continuous ( ) TPG >12 mmhg, binary ( ) PVR (WU), continuous ( ) PVR (>3 WU), binary ( ) PAC (ml/mmhg), continuous ( ) PAC <2.3 ml/mmhg, binary ( ) DPG, diastolic pressure gradient; mpap, mean pulmonary arterial pressure; PAC, pulmonary arterial compliance [stroke volume/(systolic PAP diastolic PAP)]; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; TPG, transpulmonary pressure gradient (mpap PAWP). PH-LHD patients, assessed after optimized treatment, and this may explain the lower baseline PAWP (20 vs. 24 mmhg), the lower incidence of isolated DPG increase (1.8vs.2.9%),andthehigher number of isolated PVR increase (35.1 vs. 25.9%) in our series (Tables 1 and 2) as compared with the Gerges series. 5,11 The most relevant aetiology differences between the two studies is the larger size of the HFrEF subgroups (62 vs. 9%) and the unclear number of VHD patients in the Gerges series 5,11 as compared to our study (Table 1).... Interestingly, both studies report a negative average value of DPG in patients classifiable as Ipc-PH (Table 1). 11 Negative DPG values have also been observed in other studies. 14 This outlines how the low absolute value of this parameter may facilitate random technical errors and procedural artifacts. For the above reasons, we do not suggest yet changes to the ESC/ERS PH haemodynamic definition, recognizing the uncertainties for the appropriate classification of subjects with individual increases of PVR or DPG and waiting for additional confirmatory data from other series. When we performed the Cox univariate analysis on the four parameters of interest, we confirmed a statistically significant result for binary PVR and for continuous and binary PAC, but not for DPG or TPG (Table 3). PVR and PAC are correlated (Figure 5) and it is not clear from our data which parameter is the best predictor. The limitations of our study include the retrospective analysis of a prospective single-centre registry of patients with PH. An additional bias is the referral of these patients to an expert PH centre, which may have predominantly included advanced PH-LHD cases, and patients with HFpEF or VHD, for further investigations on PH considered not justified by the severity of the underlying LHD. The performance of right heart catheterization with a standardized procedure, the selective inclusion of incident cases in the analysis, and the adjustment of fluid status by optimization of diuretic treatment before baseline right heart catheterization may have reduced the influence of these limitations. The sample size of this study has prevented a meaningful subgroup analysis according to the different aetiologies of PH-LHD. Finally, we have not analysed comorbidities and NT-proBNP plasma levels as potential confounding factors. However, in previous papers comorbidities have never been associated with the type

7 Pulmonary hypertension due to left heart disease 7 Figure 5 Correlation of baseline pulmonary vascular resistance and pulmonary artery compliance in a group of 276 patients with pulmonary hypertension due to left heart disease. Pearson correlation: r = 0.65, P < of PH-LHD, 8,17 and NT-proBNP plasma levels are correlated with RAP and PAWP that are reported in Table 1. In conclusion, the data of our study confirm that patients with PH-LHD with Ipc-PH and both normal PVR and DPG have a better outcome compared with patients with Cpc-PH and elevated PVR and DPG. Patients with an isolated increase of PVR or DPG represent an intermediate group from the clinical, functional, and haemodynamic points of view, but have a worse prognosis comparable with patients with Cpc-PH and both elevated parameters. This may influence the decision-making in this subgroup, including the indication and the risk stratification for interventional or surgical procedures. In our patient population, the prognostic value of PVR and PAC is better compared with DPG and TPG and this should be considered in future revisions of the PH guidelines haemodynamic classifications. Finally, the discrepancies of the available data on PH-LHD haemodynamic classification may be reconciled only by prospective, multicentre, adequately sized studies with pre-specified endpoints, inclusion criteria, subgroup definitions, and uniform baseline assessments and follow-up strategies. Acknowledgements Editorial assistance was provided by Lynda McEvoy, PhD, Apothe- Com Ltd (London, UK), funded by Actelion Pharmaceuticals Ltd. Funding This work was supported by the Department of Investigational, Diagnostic and Specialty Medicine, University of Bologna, Bologna,... Italy and the National Institute of Biostructures and Biosystems, Rome, Italy. Conflict of interest: none declared. References 1. Galiè N, Humbert M, Vachiery JL, Gibbs JS, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez-Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci-Cerinic M, McDonagh T, Pierard L, Trindade PT, Zompatori M, Hoeper M ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2015;46: Galiè N, Humbert M, Vachiery JL, Gibbs JS, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez-Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci-Cerinic M, McDonagh T, Pierard L, Trindade PT, Zompatori M, Hoeper M ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016;37: Vachiery JL, Adir Y, Barbera JA, Champion HC, Coghlan JG, Cottin V, DeMarco T, Galie N, Ghio S, Gibbs JS, Martinez FJ, Semigran MJ, Simonneau G, Wells AU, Seeger W. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013;62:D100 D Delgado JF, Conde E, Sanchez V, Lopez-Rios F, Gomez-Sanchez MA, Escribano P, Sotelo T, Gomez de la Camara A, de la Calzada CS. Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure. Eur J Heart Fail 2005;7: Gerges M, Gerges C, Lang IM. How to define pulmonary hypertension due to left heart disease. Eur Respir J 2016;48: Naeije R, Hemnes AR. The difficult diagnosis of pulmonary vascular disease in heart failure. Eur Respir J 2016;48: Galie N, Manes A, Palazzini M. The difficult diagnosis of pulmonary vascular disease in heart failure. Eur Respir J 2016;48: Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Fail 2013;1: Galiè N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004;25:

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