Fabio Dardi

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

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.

Combining bosentan and sildenafil in pulmonary arterial hypertension patients failing monotherapy: real-world insights

Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option. This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting. Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3–4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003). The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting. Bosentan and sildenafil combination therapy improved haemodynamics and exercise in PAH patients failing monotherapy http://ow.ly/LGrPm

Aiming at the appropriate target for the treatment of pulmonary hypertension due to left heart disease

Pulmonary hypertension (PH) due to left heart disease (PH-LHD) is defined by an increase of the mean pulmonary arterial pressure (PAP) >_25 mmHg associated with an increase in pulmonary artery wedge pressure (PAWP) >15 mmHg. Two different types of PH-LHD have been recognized from pathological, pathophysiological, and haemodynamic points of view. The first, defined as isolated post-capillary PH (Ipc-PH), is characterized by the simple backward transmission of the increased left atrial pressure through the pulmonary veins and capillaries up to the pulmonary arteries. The second subset, named combined postand pre-capillary PH (Cpc-PH), comprises a specific distal pulmonary artery disease, which contributes to a further increase of PAP as an addition to the backward transmission (Figure 1). An updated definition of the two PH-LHD haemodynamic forms was proposed in the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) PH guidelines: Ipc-PH was defined by a diastolic pressure gradient (DPG: pulmonary artery diastolic pressure minus mean pulmonary artery wedge pressure) <7 mmHg and/or pulmonary vascular resistance (PVR) <_3 Wood units (WU), while Cpc-PH was defined by a DPG >_7 mmHg and/or PVR >3 WU. Patients with Cpc-PH have a worse prognosis compared with patients with Ipc-PH, and this has been attributed mainly to the presence of the pre-capillary pathological obstructive component that affects the distal pulmonary arteries. Heart failure with reduced left ventricular ejection fraction (HFrEF), HF with preserved EF (HFpEF), and valvular heart diseases (VHD) are considered the three largest aetiological subgroups of patients with PH-LHD. In this issue of the European Heart Journal, the article of Bermejo et al. reports the results of the SIOVAC (Sildenafil for Improving Outcomes after VAlvular Correction) study, which is an investigator-driven, academically sponsored, multicentre, randomized, double-blind, placebo-controlled, parallel clinical trial (RCT) in patients with persistent PH after correction of VHD. Two hundred stable adult patients with mean PAP >_30 mmHg, who had undergone a successful valve replacement or repair procedure at least 1 year before, were randomized 1:1 to receive sildenafil (40 mg three times daily (t.i.d), n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure, change in functional class, and patient global self-assessment. The relevant message of the SIOVAC study is that treatment with sildenafil was associated with worse clinical outcomes than placebo. This conclusion is not surprising if we consider the lack of favourable clinical outcomes reported by RCTs with sildenafil either in patients with LHD or PH-LHD. The ESC/ERS PH guidelines clearly state that ‘“the use of PAH-approved therapies is not recommend in patients with PH-LHD”’, with a grade of recommendation I and a level of evidence C. As reported also in the paper of Bermejo et al., this has not prevented a large amount of off-label use of sildenafil and of other PAH-approved therapies in patients with PH-LHD. This improper attitude, based mainly on the preliminary results of small single-centre studies, has no pathological, pathophysiological, or haemodynamic rationale or multicentre RCT support (Figure 1 and Table 1). The pathological changes observed in the distal pulmonary arteries observed in PAH patients are largely different from those observed in PH-LHD patients. In the former, pathological changes predominantly affect the distal pulmonary arteries (diameter < 500 mm) with medial hypertrophy, intimal proliferative and fibrotic changes, and adventitial thickening, with mild to moderate perivascular inflammatory infiltrates and lymphoid neogenesis (Figure 1). In addition, complex lesions such as dilated and plexiform lesions are considered as a hallmark of PAH histology, and correspond to an exuberant

Anticoagulant treatment in patients with pulmonary arterial hypertension associated with systemic sclerosis: More shadows than lights

Pulmonary arterial hypertension is a chronic and progressive disease characterized by elevated pulmonary artery pressure and pulmonary vascular resistance leading to heart failure and premature death. Pulmonary arterial hypertension is characterized by proliferative and obstructive lesions in the distal pulmonary arteries and some descriptions include also thrombotic lesions. Despite this, in an era when multiple effective pulmonary arterial hypertension therapies are available, the role of anticoagulation in the treatment of pulmonary arterial hypertension remains uncertain. In particular, anticoagulant treatment in pulmonary arterial hypertension associated with connective tissue disease seems to be associated with unfavorable risk to benefit ratio due to an increased rate of bleeding from the gastrointestinal tract. However, anticoagulation may be required in conditions with increased thrombophilia like in the presence of lupus anticoagulant phenomenon or in the presence of anticardiolipin antibodies.

Pulmonary vascular disease due to left heart disease: how to achieve a more accurate approach beyond the haemodynamic phenotype: reply

Two different subsets of pulmonary hypertension due to left heart disease (PH-LHD) have been recognized from the pathological, pathophysiological and haemodynamic points of view1,2: the first, defined isolated post-capillary PH (Ipc-PH) is characterized by pure backward transmission of increased left atrial pressure through the pulmonary veins and capillaries up to the pulmonary arteries. The second form, called combined postand pre-capillary PH (Cpc-PH), includes a specific distal pulmonary artery disease, which contributes to further increase pulmonary arterial pressure as an addition to the passive component.1 Pulmonary vascular disease in patients with PH-LHD is characterized by enlarged and thickened pulmonary veins, pulmonary capillary dilatation, interstitial oedema, alveolar haemorrhage, lymphatic vessels and lymph node enlargement.3 In addition, also the precapillary circulation may be involved at the level of distal pulmonary arteries, which may be affected by different degrees of obstructive remodelling such as medial hypertrophy and intimal fibrosis and proliferation. The presence of this pre-capillary component, which is considered exclusive of the Cpc-PH form, has been described in the past3 and confirmed in more recent analyses from biopsies, autopsies and lung resections.2,4 The distal pulmonary arteries involved by these changes are typically the muscular pulmonary arteries, which have a diameter≤ 500μm and are believed to represent the main anatomical site of pulmonary circulation resistance.3,5 A debate is currently ongoing on the definition of Ipc-PH and Cpc-PH and on the best haemodynamic parameter able to capture and ‘measure’ the pre-capillary component, including diastolic pressure gradient, pulmonary artery compliance (PAC), pulmonary vascular resistance (PVR), and transpulmonary pressure gradient.1,6 In a recent paper published by our group, PVR and PAC were the only parameters to be correlated with the prognosis of PH-LHD patients.6 Grignola et al. in their letter propose to use different parameters to assess the pre-capillary component in Cpc-PH, adopting concomitant haemodynamic and intravascular ultrasound examinations and allowing to estimate pulmonary artery stiffness by the elastic modulus and to assess the relative area wall thickness. However, this technique is exploring segmental pulmonary arteries (elastic pulmonary artery ∼2–3 mm in diameter)7 and not the more distal muscular pulmonary arteries which are affected by the typical pathological changes characterizing the pre-capillary component in PH-LHD.2–5 In addition, this strategy increases the complexity and costs of right heart catheterization, reducing the likelihood of a large practical application.

Reply: Left Main Extrinsic Compression in Pulmonary Arterial Hypertension: From Identification to Percutaneous Coronary Intervention Optimization

We thank Dr. Montero-Cabezas and colleagues for the suggestions aimed to optimize the evaluation of left main coronary artery (LMCA) stenosis severity due to extrinsic compression from dilated pulmonary artery (PA) in patients with pulmonary arterial hypertension (PAH). They propose to use

Tadalafil in idiopathic or heritable pulmonary arterial hypertension (PAH) compared to PAH associated with connective tissue disease

BACKGROUND The primary objective of this post hoc analysis was to evaluate clinical outcomes of tadalafil in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD-PAH) compared with patients with idiopathic/heritable PAH (I/H-PAH) for primary and key secondary efficacy endpoints, and safety. This analysis included adult patients with CTD-PAH or I/H-PAH who participated in the PHIRST and PHIRST-2 studies. METHODS Patients were randomized 1:1:1:1:1 to tadalafil (2.5, 10, 20, or 40mg) or placebo in the PHIRST study and the majority of these patients were subsequently assigned 40mg in PHIRST-2. Patients taking 20mg in PHIRST without demonstrating clinical worsening continued on 20mg in PHIRST-2. Outcomes analyzed included 6MWD, WHO-FC, and incidence and time to first occurrence of clinical worsening. Safety was assessed through evaluation of adverse events (AEs), clinical laboratory data, electrocardiograms, and physical examinations. RESULTS Increased 6MWD in PHIRST was maintained in both CTD-PAH and I/H-PAH subgroups for 52weeks. Patients with CTD-PAH tended to be older, were more likely female, had lower exercise capacity, were more likely to have clinical worsening, and experienced AEs more frequently than patients with I/H-PAH. CONCLUSION The effect of tadalafil treatment in patients enrolled in both PHIRST studies was detectable for both I/H-PAH and CTD-PAH subgroups. In general, subgroup differences were modest. Patients with CTD-PAH may perform less well than patients with I/H-PAH in safety and efficacy measures in all treatment groups, which is similar to other studies demonstrating a worse prognosis for patients with CTD-PAH.