European Registry of Acutely Decompensated Pulmonary Arterial Hypertension

Precapillary pulmonary hypertension (PH) encompasses a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR). The international clinical classification of PH distinguishes these diseases based on their pathophysiological characteristics, clinical presentation, and management. Group 1 [pulmonary arterial hypertension (PAH)] includes diseases characterized by intense remodeling of small pulmonary arteries due to the proliferation of endothelial and smooth muscle cells (1). Within this group, we distinguish isolated pulmonary vascular diseases without comorbidity (idiopathic PAH, "familial" or hereditary PAH, and PAH associated with drug and toxin use) and PAH associated with a concomitant pathology (connective tissue diseases, congenital heart diseases, portal hypertension, HIV infection, schistosomiasis, chronic hemolytic anemias). This distinction is primarily based on the progressive profile of these different conditions. Other forms of precapillary pulmonary hypertension include PH associated with respiratory disease (Group 3), postembolic PH (Group 4), and multifactorial PH (Group 5). Group 2 concerns postcapillary PH, i.e., related to left heart diseases.

Over the past twenty years, PAH has benefited from significant therapeutic innovations resulting from a better understanding of the pathophysiological mechanisms associated with this disease. The currently available treatments primarily target endothelial dysfunction of the pulmonary arteries (2). New therapeutic approaches aiming to reduce pulmonary vascular proliferation in addition to the already available medications are in development. The most advanced therapeutic innovation targets abnormalities related to the receptors of the TGF-ß superfamily (3,4). However, despite the undeniable progress made in the last 20 years, PAH remains an incurable disease that progresses to right ventricular failure and death. The latest epidemiological data from the French PH registry estimate a 25% mortality rate at 3 years (5).

The ability of the right ventricle (RV) to adapt to the progressive increase in PVR is the key prognostic factor for patients with PH (6). The RV's adaptation to excessive afterload begins with concentric myocardial hypertrophy, aiming to normalize the imposed wall stress. Subsequently, the RV dilates in response to increased pressures. The eccentric hypertrophy combined with excessive dilation of the right cavities often reflects a so-called "maladaptive" phenotype. At this stage, severe systolic and diastolic dysfunction of the RV is observed, associated with left ventricular (LV) diastolic dysfunction due to RV/LV interdependence mechanisms. This phenotype corresponds to the final stage of PH, characterized by the onset of NYHA functional class III or IV dyspnea, the appearance of congestive signs, a risk of syncope, and hemodynamically by chronic elevation of right atrial pressures and a decrease in cardiac output. All these clinical, functional, and hemodynamic parameters are closely correlated with a poor prognosis and result from severe impairment of ventriculo-arterial coupling (1).

Patients in the terminal phase of precapillary PH are thus at high risk of developing acute right heart failure, which is predominantly observed in patients with PAH. This clinical situation corresponds to an imbalance of the RV's adaptive phenomena, leading to an acute worsening of symptoms, typically associated with circulatory failure and, in the most severe cases, multiple organ failure. Despite the highly unfavorable prognosis of this clinical situation (7,8), there is currently no precise consensus on the management of these patients. Their care primarily involves identifying and treating any potential triggering factor, optimizing RV preload, and using inotropes if necessary to improve right ventricular performance and stabilize systemic blood pressure. Alongside symptomatic management, the possibility of intensifying specific PH treatment is systematically considered, aiming to reduce RV afterload (9,10).

Despite this management, some patients develop a scenario of refractory right ventricular failure. Therapeutic options for these patients, which were nonexistent 15 years ago, have significantly developed in recent years with circulatory support on one hand, and emergency heart-lung or double-lung transplantation on the other. Since 2006 for heart-lung transplantation and 2007 for double-lung transplantation, the Biomedicine Agency has implemented a "super-urgent" program allowing these patients, in a situation of acute refractory decompensation despite optimal medical treatment, to have priority access to available grafts within the national territory for a renewable period of 8 days. For the most severe patients, veno-arterial extracorporeal membrane oxygenation (ECMO) circulatory support can be implemented while waiting for transplantation. Currently, this procedure is used in about 20% of patients awaiting heart-lung or double-lung transplantation under super-urgent status for PH.

This therapeutic approach has improved the survival of patients hospitalized in intensive care for acute decompensation of pulmonary hypertension and candidates for transplantation (8). It underscores the importance of managing these patients in expert centers capable of offering all possible therapeutic options, whether medical, interventional, or surgical. One of the key points in managing acute right heart failure in PH involves clinical, hemodynamic, and biological monitoring, necessary to evaluate the patient's prognosis, adapt initiated therapies, and decide on emergency transplantation and/or circulatory support in cases of refractory right ventricular failure.

However, there are likely significant disparities in the management of these patients depending on the organization of care pathways, graft allocation rules, and access to circulatory support. The objective of this clinical research collaboration is to study the prognostic implications of decompensated acute right heart failure associated with PAH using a large-scale, multicenter European approach with prospective analysis of clinical, biological, and echocardiographic data.

3.2. Description of the Elements Under Study The study population consists of patients admitted for acute decompensation of PAH requiring treatment with intravenous diuretics, combined with the use of catecholamines if necessary. This study will in no way influence the management of these patients.

Acute decompensation of right ventricular failure will be defined by the worsening of clinical signs of right heart failure within the month preceding hospital admission, requiring:

• the use of i.v. diuretics for ≥ 2 days
• or inotropes
• or vasopressors This cohort study aims to collect clinical, biological, and echocardiographic data from at least 200 patients admitted for an episode of acute decompensation of PAH within multiple European centers belonging to the ERN-Lung network. Information regarding their therapeutic management during hospitalization and their status (alive without transplantation, transplanted, deceased) at 3 months and one year after inclusion will also be collected. This study will enable the analysis of the prognosis of these patients and the identification of prognostic factors based on the collected parameters.

Feasibility and Consistency of the Working Group This project is part of the European clinical research collaboration project PHAROS, supported by the European Respiratory Society (ERS) and closely related to the European Rare Disease Network ERN-Lung.

The investigative centers participating in this study are part of the ERN-Lung network and have already collaborated on this topic, particularly by participating in a survey on the management of acute decompensations of pulmonary hypertension. The results of this survey were presented at the latest European Respiratory Society congress in September 2023 (Savale et al, "Management of acute decompensated pulmonary arterial hypertension: results of the ERS Clinical Research Collaboration PHAROS survey").

Expected Results and Perspectives / Hypotheses / Justification of Public Interest Currently, there are very few studies, primarily retrospective, single-center, and with small sample sizes, that describe the characteristics of patients with acute decompensation of PAH and their prognosis. Recent developments in the management of these patients, especially with the advancement of circulatory support in right ventricular failure and changes in graft allocation rules, necessitate further understanding of the characteristics of these patients and their prognostic parameters.

The goal is to improve the management of these patients and better identify potential candidates for emergency transplantation and/or circulatory support. The European ERN-Lung network provides a unique opportunity to gather data from multiple centers and constitute a cohort large enough to identify prognostic parameters that are relevant for the management of these patients.