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with an LV ejection fraction of 40–60%.682 Endothelin receptor antagonists have not proved successful in this population, as both bosentan683 and macitentan684 failed to show efficacy but rather led to more adverse events (fluid retention) vs. placebo in patients with HFpEF-associated PH and HF with ejection fraction .35%-associated CpcPH, respectively. Phosphodiesterase 5 inhibitors were assessed in two small RCTs in patients with HFpEF and PH with distinct haemodynamic characteristics. In patients with a predominantly IpcPH profile, sildenafil had no effect on mPAP (primary endpoint) or other haemodynamic and clinical measures vs. placebo.685 In patients with a predominantly CpcPH profile, sildenafil improved haemodynamics, RV function, and quality of life at 6 and 12 months vs. placebo.686 Furthermore, retrospective analyses and registry data suggested improvements in exercise capacity with PDE5i therapy in patients with HFpEF-associated CpcPH and with a severe pre-capillary component (PVR mostly .5 WU).450,687

8.3.1.3 Interatrial shunt devices

Recent data suggest that specific interventions may be considered in selected cases of HFpEF, such as interatrial shunt devices to unload the left heart. While this was associated with short-term improvements in pulmonary vascular function,688 the long-term effect on the pulmonary circulation remains unknown. The recent REDUCE LAP-HF II trial failed to show a reduction in HF events after placement of an atrial shunt device in a population of HF patients with LVEF ≥40%,689 with worse outcomes in the presence of PVD.690 In addition, a sustained increase in PA blood flow may be a matter of concern, as this may trigger vascular remodelling in patients with pre-existing PH.

8.3.1.4 Remote pulmonary arterial pressure monitoring in heart

failure The importance of decongestion in patients with HF is underscored by the use of implantable pressure sensors, remotely monitoring PAP as a surrogate of left-sided filling pressure. Pulmonary arterial pressure-based adjustment of HF therapy substantially reduced HF hospitalizations and improved outcomes in both patients with HFpEF and HFrEF,691–694 with adjustment of diuretic therapy being the most prominent therapeutic consequence. Further strategies to optimize management depending on the haemodynamic phenotype in PH-LHD remain to be established. In HFrEF, novel medical therapies such as ARNIs and SGLT-2is reduced remotely monitored PAP and diuretic use,695–698 potentially providing opportunities to further optimize PAP-guided HF therapy.

8.3.2 Pulmonary hypertension associated with

valvular heart disease Pulmonary hypertension frequently occurs as a consequence of valvular heart disease. While surgical or interventional approaches for valvular repair improve cardiopulmonary haemodynamics by reducing PAWP and PAP and improving forward SV,699 persistent PH after correcting valvular heart disease is frequent and associated with adverse outcomes.634,700

8.3.2.1 Mitral valve disease

Both mitral stenosis and regurgitation regularly lead to post-capillary PH. Functional (secondary) mitral regurgitation occurs in both HFrEF and HFpEF, and is an important contributor to PH in LHD. Reducing mitral regurgitation according to the recommendations of the 2021 ESC/EACTS Guidelines for the management of valvular heart disease28 has a crucial role in improving haemodynamics in patients with HFrEF, as this reduces mPAP and PAWP and improves the CI.699 Nevertheless, registry data have demonstrated that even moderately elevated sPAP negatively impacts post-procedural outcomes after catheter-based therapy.700

8.3.2.2 Aortic stenosis

In patients with aortic stenosis undergoing surgical or catheter-based aortic valve repair, pre-interventional PH is associated with a higher risk of in-hospital adverse events and adverse long-term outcomes.646–651 Although post-procedural improvement in PH correlates with symptom relief and favourable outcomes, persistence of PH is common, and even moderate PH is associated with a higher all-cause mortality.646–651 Of note, medical therapy of PH post-valvular repair may be harmful. A randomized study of 231 patients with surgically corrected valvular heart disease and persistent PH showed that sildenafil therapy vs. placebo was associated with worse outcome when compared with placebo;701 however, this study did not distinguish between different types of PH (pre-capillary, IpcPH, and CpcPH).

8.3.2.3 Tricuspid regurgitation

Severe TR is associated with volume overload, increased RV workload, and maladaptive remodelling, leading to symptomatic right HF and impaired survival.702,703 While primary TR is relatively rare, functional TR may arise from annular dilation in the presence of both PH and LHD. Transcatheter tricuspid valve interventions have recently emerged, aiming at reducing TR and RV volume overload. Of note, correcting TR in patients with PAH or PH in (non-valvular) LHD with significantly elevated PVR and/or RV dysfunction must be considered with great caution, as this may be hazardous.704 Right ventricle– PA coupling is an independent predictor of all-cause mortality in such patients.705 Patient selection appears crucial, and a comprehensive diagnostic approach integrating imaging modalities and invasive haemodynamic assessment is necessary in the evaluation process prior to tricuspid valve repair, particularly since echocardiography underestimates sPAP in the presence of severe TR.

8.3.3 Recommendations on the use of drugs

approved for PAH in PH-LHD The recommendations on the use of drugs approved for PAH in patients with PH-LHD have been established based on key narrative question 5 (Supplementary Data, Section 8.3). The recommendations on the use of PDE5is in patients with CpcPH associated with HFpEF are based on PICO question II (Supplementary Data, Section 8.4). Two RCTs that enrolled patients with HFpEF and PH were identified, but no study that specifically enrolled patients with HFpEF and CpcPH. Harmful effects cannot be excluded, even if the available data from clinical studies, case series, and registries suggest that PDE5is may be safely administered to patients with HFpEF-associated CpcPH. As a result, a general recommendation for or against the use of PDE5is in patients with HFpEF and CpcPH cannot be made. However, it is clinically relevant to make a recommendation against their use for patients with HFpEF and IpcPH. Downloaded from academic.oup.com/eurheartj/article/43/38/3618/6673929 by guest on 07 October 2026