Abstract
Pulmonary hypertension physicians must embrace this new and exciting aspect of clinical care of PAH patients for the benefit of our present and future patients https://bit.ly/3pf7GhG
It has been over 20 years since the discovery of heterozygous germline mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) in families with pulmonary arterial hypertension (PAH) [1, 2]. Much has been learned since then regarding how mutations in BMPR2 cause PAH, although many questions remain unanswered. Mechanistically, loss of BMPR2 signalling in vascular cells, and particularly endothelial cells, greatly increases the likelihood of initiating the characteristic vascular pathology seen in the lungs of patients with PAH [3]. Although asymptomatic carriers of BMPR2 mutations are at markedly increased risk of developing PAH (at least 10 000-fold greater risk than non-carriers), one of the features of BMPR2 mutations is that they exhibit reduced penetrance [4]. In other words, carriers of BMPR2 mutations do not inevitably develop PAH. This is of great interest scientifically because it implies the need for additional “triggering” factors in the context of BMPR2 mutations that are required in order for disease to develop. The potential triggering factors identified to date come from in vitro studies of patient-derived cells and in genetically modified mice [5, 6]. Inflammation-induced injury seems to stimulate a greater degree of pulmonary vascular remodelling in BMPR2 deficient mice than in wild-type littermates, and BMPR2 deficient mice possess an exaggerated inflammatory response to injury [7]. This amplification of certain inflammatory pathways may initiate and propagate the vascular changes. In addition, the presence of a BMPR2 mutation in pulmonary vascular endothelial cells increases susceptibility to apoptosis and increases vascular permeability in response to injury [8–10]. These extrinsic factors act to further suppress BMPR2 signalling, or exacerbate a dysfunctional endothelium already primed by the presence of mutation.
The study of non-affected carriers of BMPR2 mutations is of great scientific and clinical importance, and yet is extremely challenging. To begin such a study requires the identification of a large number of individuals with PAH and BMPR2 mutations. This requires a pulmonary hypertension service in which genetic testing is embedded into the clinical management of patients, or there exists a research effort to identify BMPR2 mutation carriers within a PAH cohort. Although recent clinical PAH guidelines recommend genetic counselling and testing of patients with heritable or idiopathic PAH [11], this recommendation is taken up unevenly across Europe and the USA. The reasons for this slow uptake of genetic testing in pulmonary hypertension services vary, but an important factor is the reluctance of physicians to consider genetic testing of PAH patients, perhaps based on lack of knowledge and lack of experience with initiating a conversation around genetics. Physicians should bear in mind the willingness of PAH patients to engage in this conversation: a recent survey of patients (n=211) with idiopathic PAH undertaken by the UK Pulmonary Hypertension Association found that 74% of respondents would want to be referred for genetic testing if they knew there was a chance of their PAH being caused by a faulty gene [12].
The French National Pulmonary Hypertension Service centred in Paris is one of the pioneers of clinical genetic testing in PAH and has embraced this recommendation for several years, leading to the identification of a large cohort of BMPR2 PAH patients [13]. Similar efforts are underway in the Netherlands and the UK [14, 15], and elsewhere. It is worth remembering that there are many more “idiopathic” sporadic PAH patients with BMPR2 mutations than cases of familial PAH with BMPR2 mutations. Genetic testing of sporadic apparently “idiopathic” cases reveals that 20–25% are in fact examples of heritable disease [16].
Once a cohort of affected BMPR2 mutation carriers is identified, the next step is to offer cascade genetic testing of family members, whether or not there is a family history of disease. The discussion with the relatives will include the risks of developing PAH. If a relative tests negative for a BMPR2 mutation, then their risk of developing PAH is similar (as far as we know) to that of the general population (annual incidence 1–2 cases per million per year). Conversely, if they test positive for a BMPR2 mutation then the risk is massively increased. Penetrance of PAH is different in males and females. In males the available estimates of penetrance suggest a 15% lifetime risk, whereas this rises to 40% in females [17, 18]. Apart from female sex, we do not yet know the factors that influence penetrance in individuals carrying BMPR2 mutations. One can imagine that the pool of non-affected individuals carrying pathogenic BMPR2 mutations is quite large, approaching the number of patients with idiopathic and heritable PAH, depending on the size of families. These individuals can be likened to the part of the iceberg that sits below the waterline, with a proportion manifesting as overt PAH each year (figure 1). At present there are no strategies or trials directed at preventing the manifestation of PAH in BMPR2 mutation carriers. For example, we do not know whether any of the existing licensed therapies are capable of preventing the development of PAH in these patients. With more widespread genetic testing of patients and their families, such trials will be possible.
In this issue of the European Respiratory Journal, Montani et al. [19] report the results of a cohort (n=55) of asymptomatic BMPR2 mutation carriers followed up for at least 2 years as part of the DELPHI-2 study. One of the remarkable features of this study is that all of these asymptomatic subjects consented to undergo right heart catheterisation at study entry. This revealed mild resting PAH in two asymptomatic subjects. During the 2 years of mandatory follow-up, no additional cases were identified. However, 36 subjects consented to extended follow-up as part of usual care. Amongst this group, three additional cases of PAH were diagnosed in the 6 years following study entry. Overall, the authors found that 9.1% of asymptomatic BMPR2 mutation carriers developed PAH within the study period, with a higher risk in females (13.8%) versus males (3.8%), representing an overall incidence of 2.3% per year. At first sight this seems to be a small number, but the implications are hugely important: based on these data, over a 10-year period we might expect 23% of BMPR2 mutation carriers to develop PAH. Firstly, this further justifies the adoption of routine screening programmes for asymptomatic BMPR2 mutation carriers as part of the clinical care provided by pulmonary hypertension centres. Secondly, if we can detect disease at an early stage in these individuals, we may be able to impact favourably on the course of disease [20]. In keeping with this, the five PAH patients diagnosed by the DELPHI-2 screening programme and commenced on oral combination therapy remained in a low-risk category according to validated risk scores after 6 years.
The DELPHI-2 screening programme consisted of baseline and subsequent yearly visits. The investigations undertaken at each study visit were quite extensive, including physical examination, ECG, chest radiography, 6-min walking distance, pulmonary function testing, cardiopulmonary exercise test, echocardiography and N-terminal pro-BNP, with an optional right heart catheterisation at baseline. In addition, subjects were encouraged to contact the investigators if they experienced any unexplained dyspnoea, malaise or syncope. The investigators found that no single test was capable of reliably predicting the onset of early PAH. In particular, echocardiography was normal in all subjects at baseline, including those who subsequently were diagnosed with PAH. In the three subjects who developed PAH in the 6 years of follow-up, echocardiography became abnormal (tricuspid regurgitation velocity >2.8 m·s−1), with signs of PAH on ECG and two cases were suspected on the basis of cardiopulmonary exercise testing. The investigators recommend that further international studies are undertaken with a similar multimodality screening programme for PAH in asymptomatic carriers to establish the most informative screening modality. This recommendation should be welcomed. In addition, such studies will provide an opportunity to identify risk factors for disease penetrance and potential circulating biomarkers that might eventually replace the need for multimodality screening.
One of the inescapable implications of the DELPHI-2 study is that we can no longer ignore the role of genetic testing in PAH and the need to adopt protocols for screening asymptomatic relatives of BMPR2 mutation carriers. Pulmonary hypertension physicians must embrace this new and exciting aspect of clinical care of PAH patients for the benefit of our present and future patients.
Shareable PDF
Supplementary Material
This one-page PDF can be shared freely online.
Shareable PDF ERJ-00286-2021.Shareable
Footnotes
Conflict of interest: N.W. Morrell reports grants and personal fees from Morphogen-IX, outside the submitted work.
Support statement: This work was supported by the British Heart Foundation and the National Institute for Health Research. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received January 29, 2021.
- Accepted January 30, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org