Impact of the new pulmonary hypertension definition on long‐term mortality in patients with severe aortic stenosis undergoing valve replacement

Abstract Background The new 2018 pulmonary hypertension (PH) definition includes a lower mean pulmonary artery pressure (mPAP) cut‐off (>20 mmHg rather than ≥25 mmHg) and the compulsory requirement of a pulmonary vascular resistance (PVR) ≥3 Wood units (WU) to define precapillary PH. We assessed the clinical impact of the 2018 compared to the 2015 PH definition in aortic stenosis (AS) patients undergoing aortic valve replacement (AVR). Methods Severe AS patients (n = 487) undergoing pre‐AVR right heart catheterization were classified according to the 2015 and 2018 definitions. Post‐AVR mortality (median follow‐up 44 months) was assessed. Results Based on the 2015 definition, 66 (13%) patients exhibited combined pre and postcapillary PH (CpcPH), 116 (24%) isolated post‐capillary PH (IpcPH), 28 (6%) precapillary PH, and 277 (57%) no PH at all. Overall, 52 (11%) patients were reclassified: 23 no PH into IpcPH; 8 no PH into precapillary PH; 20 precapillary PH into no PH; 1 CpcPH into IpcPH. By the 2015 definition, only CpcPH patients displayed increased mortality, whereas by the 2018 definition, precapillary PH patients also experienced higher mortality than those without PH. Among the PH definition components, PVR ≥3 WU was the strongest predictor of death (hazard ratio > 4). Conclusions In severe AS, a higher number of IpcPH patients are diagnosed by the 2018 definition, even though they have the same prognosis as those without PH. Patients with true precapillary PH are more accurately identified by the 2018 definition that includes a pulmonary vascular disease criterion, that is, PVR ≥3 WU, a strong mortality predictor.


| INTRODUCTION
The 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines define any pulmonary hypertension (PH) as a mean pulmonary artery pressure (mPAP) ≥25 mmHg, and a mean pulmonary artery wedge pressure (mPAWP) ≤15 mmHg versus >15 mmHg is applied to differentiate precapillary from post-capillary PH. 1 It has, however, been argued that the mPAP cut-off of 25 mmHg is too high, given that the upper limit of a normal mPAP is approximately 20 mmHg, 2,3 and because studies have revealed higher mortality in patients with mPAP 21-24 versus ≤20 mmHg, 4,5 as well as in patients with mPAP 19-24 versus ≤18 mmHg. 6,7 In addition, the definition of precapillary PH solely based on an elevated mPAP in combination with a nonelevated mPAWP, that is, ≤15 mmHg, was criticized, because this definition does not include a marker of a pulmonary vascular abnormality. 3 The 6th 2018 PH World Symposium, therefore, proposed a new PH definition including the following key elements: (1) lower mPAP cut-off (>20 mmHg rather than ≥25 mmHg); (2) compulsory requirement of pulmonary vascular resistance (PVR) ≥3 Wood units (WU) for defining precapillary PH. 3 In addition, the 2018 definition suggests not using any longer the diastolic pressure gradient (DPG) for differentiating isolated post-capillary (IpcPH) from combined pre and postcapillary PH (CpcPH), but instead only the PVR ≥3 WU criterion (previously: PVR >3 WU). 8 The underlying reasons are as follows: (1) high prevalence of negative DPG values that cause confusion; (2) contradictory data concerning the prognostic value of DPG (recently summarized by Lang 9 ). 8 This new definition is under intense discussion. [10][11][12][13] Arguments against adopting it include potential PH overdiagnosis and overtreatment, and that the change in definition affected only the mPAP cut-off, whereas the mPAWP and PVR cut-offs for hemodynamic group classification were left unaltered despite evidence showing that the upper limit of normal may possibly be lower for these parameters. 10 For example, it has been shown recently that the risk of death is already rising at a PVR cut-off of 2.2 WU. 14 There is, however, still little data on the clinical impact of this new PH definition in terms of reclassification rates and prognosis. 15

| Cardiac catheterization
Procedures were generally (>95%) performed between 8 and 10 a.m., with the patient in the fasting state and after withholding loop diuretics and renin-angiotensin system inhibitors. Patients underwent coronary angiography using 5-or 6-French catheters via femoral or radial artery access, and right heart catheterization using 6-French Swan-Ganz catheters via femoral or brachial access. Routine right heart catheterization at the time of coronary angiography has been our practice for more than 20 years in patients with AS evaluated for AVR. The midthoracic level was used as zero reference point. Systolic pulmonary artery pressure (sPAP), diastolic pulmonary artery pressure (dPAP), mPAP, and pulmonary artery wedge pressure were measured.
Measurements were obtained at end-expiration, while avoiding patient's breath-holding and especially Valsalva maneuvers, with the mean of three to five measurements taken. The mPAWP was calculated over the entire cardiac cycle, and V waves were included. This practice leads to higher values compared to the measurement of the end-diastolic pulmonary artery wedge pressure. However, for the estimation of the impact of the left heart contribution to pulmonary pressures and calculation of PVR respectively, mPAWP is preferred. 23 In patients with atrial fibrillation, at least five cardiac cycles were used to average pulmonary artery pressure and pulmonary artery wedge pressure. Cardiac output was assessed by the indirect Fick method based on blood gasses, with blood samples taken in duplicate via arterial access and pulmonary artery catheter. Diastolic pressure gradient was calculated as the difference between dPAP and mPAWP, and transpulmonary gradient as that between mPAP and mPAWP, and PVR as transpulmonary gradient divided by cardiac output. All pressure readings were double-checked by the operator using manual review of the pressure tracings before recording them into the report.

| Hemodynamic definitions
According on the 2015 ESC/ERS guidelines, 1 24 According to the 2018 proposal 3,8 IpcPH is defined as mPAP >20 mmHg, mPAWP >15 mmHg, and PVR <3 WU; CpcPH as mPAP >20 mmHg, mPAWP >15 mmHg, and PVR ≥3 WU; precapillary PH as mPAP >20 mmHg, mPAWP ≤15 mmHg, and PVR ≥3 WU. Patients with mPAP >20 mmHg, mPAWP ≤15 mmHg, and PVR <3 WU do neither fulfill criteria for precapillary PH nor for post-capillary PH. This group of patients is not addressed in the 2018 definition papers, 3,8 and it is not explicitly stated either whether any patient with mPAP >20 mmHg should be classified as having PH. Therefore, we assumed that these patients do not have PH as there is not clear evidence for pulmonary vascular disease and/or elevated left atrial pressure.
Information on long-term follow-up was obtained from patients, general practitioners, and hospital or practice cardiologists. The endpoint was all-cause mortality.

| Statistical analysis
Categorical data were presented as numbers and percentages, and continuous data as mean ± standard deviation or median (interquartile range), as appropriate. Patients from different hemodynamic PH categories and those without PH according to the 2015 and 2018 definitions were compared using chi-square tests, analysis of variance, or Kruskal-Wallis tests, as appropriate. Survival of patients from different PH groups and different hemodynamic categories were compared using Kaplan-Meier plots and log-rank tests. Cox regression was applied to describe the association between variables of interest and mortality. A p-value <.05 was considered statistically significant. Analyses were performed using SPSS statistical package Version 20.0 (SPSS Inc., Chicago, IL, USA).

| Reclassification
Overall, 52 (11%) patients out of 487 were reclassified after applying the 2018 definition instead of 2015 definition, that is, 23 patients from no PH to IpcPH, eight from no PH to precapillary PH, 20 from precapillary PH to no PH, and one patient from CpcPH to IpcPH   those without PH (Figure 2(B)). According to both definitions, any PH was associated with increased long-term mortality after AVR ( Figure S2). Overall, reclassified patients had a similar mortality compared to nonreclassified patients ( Figure S3).

| Prognostic impact of different hemodynamic cut-offs
The prognostic impact of the single hemodynamic parameters contributing to the PH definitions is shown in Figure 3. had similar mortality as those without PH. 16 The setting of our study differed from these studies, 15 Stroke volume index (ml/m 2 ) 29 ± 9 36 ± 10 34 ± 9 40 ± 8 <.001 Note: Data are given as numbers and percentages, mean ± SD, or median (interquartile range). Abbreviations: ACEI/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker, AVR, aortic valve replacement; E/e', ratio of peak early mitral inflow velocity to peak early mitral annular velocity, eGFR, estimated glomerular filtration rate; FEV1, forced expiratory volume within the first second; mPAP, mean pulmonary artery pressure; mPAWP, mean pulmonary artery wedge pressure; NYHA, New York Heart Association; sPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion.  which had previously been proposed 27,28 (but not supported any more 2 years later 29 ) with the intention to avoid unclassifiable patients and to select "true" CpcPH patients. However, this study included considerably less post-capillary PH patients than the present one and did not report outcome data. 17 As outlined above based on more recent prognostic data 24 we applied the PVR >3 WU and/or DPG ≥7 mmHg criterion for the 2015 definition of CpcPH, and the poor prognosis of CpcPH patients selected by this criterion (Figure 3(A)) seems to support our practice.
F I G U R E 4 Kaplan Meier plots showing cumulative events (mortality) according to single hemodynamic parameters [three categories; tertiles for mean pulmonary artery wedge pressure (mPAWP) and diastolic pressure gradient (DPG), cut-offs of interest for mean pulmonary artery pressure (mPAP), and pulmonary vascular resistance (PVR)]. HR: hazard ratio, 95%CI: 95% confidence interval One of the strengths of the current study is that this is the only available study in a group 2 PH setting examining hemodynamic data in relation to long-term prognostic information. According to both the 2015 1 and 2018 3 definitions, mortality of IpcPH patients did not differ from that of patients without any PH. Importantly, patients "without PH" (comparator group) were not to be seen as normal subjects, as they also exhibited a left ventricle that was exposed to chronic pressure overload. In IpcPH patients, the AVR-induced afterload

| Limitations
First, the number of patients in the different PH groups was relatively small and too low to come to a definite conclusion regarding the new definition's prognostic impact. Although we found similar mortality in patients with PVR <2 WU and those with PVR 2-3 WU, it remains possible that the risk of death may be rising at PVR values less than 3 as shown for other populations. 14 Nevertheless, this is one of the first larger-scale studies designed to assess the possible impact of the new PH definition including its prognostic implications and the first one in AS patients as a typical example of an important left heart disease. Second, to assess cardiac output, we have employed the indirect Fick method, which may be subject to error, as oxygen consumption is often inaccurately estimated. 30 This has implication for the calculation of PVR, that is, an underestimation of PVR if cardiac output it overestimated and vice versa. It must, however, be noted that this technique is routinely used in clinical practice. Third, we acknowledge that mPAWP results may vary depending on the methodology, for example, on the measurement during the respiratory cycle (end-expiratory versus averaging over several cycles). 31 Experts agree that averaging mPAWP over three respiratory cycles is also acceptable as opposed to end-expiratory measurements. 32 Finally, our assumption that the patients with mPAP >20 mmHg, mPAWP ≤15 mmHg, and PVR <3 WU, which is not explicitly addressed in the 2018 definition paper, can be labeled as "no PH" may be subject to discussion as this is not explicitly stated either. We hope that this will be clarified in future recommendations and guidelines.

| Conclusions
In severe AS, the new PH definition diagnoses a higher number of patients as having IpcPH, even though their prognosis is similar to that observed in patients without any PH. Patients with true precapillary PH are more accurately identified by means of the 2018 proposal that includes a pulmonary vascular disease criterion defined as PVR ≥3WU, which is a strong predictor of poor prognosis.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author (MTM) upon reasonable request.