Gaps of Evidence in Pulmonary Hypertension: The usefulness of Registries
Summary from Alessandra Cuomo and Valentina Mercurio
GROUP 1 PH
Risk stratification in PAH
by Olivier Sitbon
Professor Sitbon opened the meeting with his presentation on the importance of risk stratification in PAH. Multiple risk equations and models are available to predict outcomes and guide management in PAH. Among them, he cited the REVEAL 2.0 risk score that can predict both survival and clinical worsening. Then, he showed the results of the application of short versions of the risk assessment tool from ESC/ERS guidelines’ table from the Swedish PAH Registry and the COMPERA Registry. He also discussed the French approach that consists of counting the number of low-risk criteria (even non-invasive criteria) in order to identify patients with a better prognosis. These approaches are useful both at baseline, and at follow-up and have been further validated in cohorts from cornerstone randomised controlled trials such as, PATENT-1 and -2, GRIPHON.
Professor Sitbon also showed preliminary results from the EFORT Study (recently presented at the latest ERS Conference in Madrid), the first multicentre prospective study in the French Pulmonary Hypertension Network aimed at analysing the transplant-free survival of a cohort of newly diagnosed treatment-naïve patients with idiopathic, heritable or drug-induced PAH. Alongside, identifying prognostic factors and cut-off values using a dynamic survival-prediction model, including variable assesses at pre-specified follow-up timepoints. The study demonstrated that achieving at least 2 goals, at any time, decreased the instantaneous risk of death or lung transplantation.
Furthermore, Professor Sitbon discussed the limitations of the risk assessment tool from the ESC/ERS guidelines table. Indeed, the presence of overlap patients makes the table blurring and he recommended to also add the clinical experience and clinical impression.
Clinical Impact of Genetics in PAH
by Stefan Gräf
Professor Gräf gave an interesting overview of molecular genetics network in PAH.
Heterozygous mutations in BMPR2 could represent a risk factor for precipitation and progression of PAH. Next generation sequencing could be useful in understanding the genetic architecture of PAH in order to provide new potential for the development of novel, precision medicine options in PAH management.
Genome sequencing is becoming routine, but the analysis of non-coding genes is very challenging. It is important to look at large scale reference populations in order to improve the understanding of a rare disease. Professor Gräf showed some interesting data from the NIHR BioResource Rare Disease (a pilot project of the Genomics England) whole genomes’ analysis from 13037 individuals allowed to identify 1148 genes variations involved in the domain of PAH. The majority of these variations are rare, and their distribution is various. He underlined that in the last ten years the number of genes discovered that are associated with PAH has more than tripled. In this regard, he highlighted the importance of increasing cohort size to further empower the identification of genetic factors in PAH by sharing data with other institutions such as the American PAH BioBank, and by integrating with complementary datasets, like other -omics or clinical features.
Professor Gräf also described the importance of combining the genetic information with PAH phenotypes by means of BeviMed analysis. As future directions, he cited 13 task forces from the international consortium for genetic studies in PAH (PAH-ICON).
Finally, Professor Gräf emphasised the role of clinical genetics as part of routine patient care, and the clinical implications of genetic assessment in PAH, especially focusing on genetic education and counselling.
PAH-CHD: From childhood to adulthood
by Sheila Glennis Haworth
Professor Haworth gave a nice overview of PAH associated with congenital heart disease (CHD). CHD concerns all ages (with different prevalence) and pulmonary vascular disease in CHD can be quite heterogeneous. She focused on the impact of genetic mutations in the development of CHD-PAH. Recent data strongly implicates SOX17 as a new risk gene contributing to PAH-CHD (SOX17 variant in 3.2% of PAH-CHD cases). For example, some patients with atrial septum defects (ASD) with PAH, have mutations in high-risk genes including SOX17. A specific genetic background may in part, explain why only some patients with ASD develop PAH.
TBX4 (T-box 4) mutations are associated with small patella syndrome in children but are also implicated in lung development. Nevertheless, there is still poor knowledge on the interactions between genetics and CHD. In this regard, multicentre, international registries are needed. Professor Haworth then discussed the need of defying the threshold of PVR in order to choose the correct treatment option. Acute vasoreactivity tests should be used only to decide if patients are responsive to calcium channel blockers, not to decide whether the patient needs surgery or does not. Postoperative CHD should be treated like idiopathic or hereditable PAH (also with the same aggressive approach).
Professor Haworth also examined the greatest dangers for patients with CHD-PAH, including pregnancy, surgery, comorbidities, and polypharmacotherapy with potential interactions with PH drugs. She showed some data from Nordic Countries’ experience on the prevention of Eisenmenger syndrome. At the end of her presentation she underlined the need for detailed CHD-PAH registries aimed at deep phenotype CHD-PAH patients.
GROUP 2 PH - Which are the Group 2 PH patients to be enrolled in a trial with pulmonary vasodilators?
by Stefano Ghio
Professor Ghio started his presentation by stating that this is a million-dollar question. Indeed, pulmonary hypertension due to left heart disease (PH-LHD) is the most common form of PH, but also the one with less therapeutic options besides treatment of the underling heart disease, and that there are several gaps in knowledge and controversies to be addressed in order to answer the question.
The first issue is choosing the proper hemodynamic definition of PH-LHD, and, in particular, the proper threshold for pulmonary capillary wedge pressure to define post-capillary PH, which is, according to the guidelines, >15mmHg. However, in some cornerstone studies, this cut-off has been set at ³12 mmHg or even less. The second issue is understanding the pathophysiological mechanisms of PH-LHD. The development of PH in LHD is caused by backward transmission of high filling pressure, “followed” by (or even associated with) superimposed reactive increase in vascular resistance. Nevertheless, it is not yet clear if this mechanism is time-dependent, patient-dependent or even both. From a genetic standpoint, it has been demonstrated that there are some single-nucleotide polymorphisms shared between PAH and combined post- and pre-capillary PH.
On the other hand, a recent study showed that the histopathologic changes in PH-LHD are more similar to the one that lead to PH associated with pulmonary veno-occlusive disease than to PAH. Other than these observations, Professor Ghio focused on the importance of understanding whether the disproportional increase in pulmonary pressures is due to vasoconstriction or is due to the presence of an actual and irreversible pulmonary vascular disease. Indeed, several studies demonstrated that the presence of irreversible pulmonary vessels disease in patients waiting for heart transplantation has relevant implications in term of prognosis.
The third issue to be addressed is which hemodynamic profile should be chosen to identify patients to include in clinical trials? So far, there is no identification on specific subgroups of patients who might respond better to specific pulmonary vasodilator therapy. PH associated to heart failure with reduced ejection fraction has different physiopathology and haemodynamics in comparison to heart failure with preserved ejection fraction (HFpEF).
Furthermore, the mechanisms that have lead to the development of right ventricular dysfunction may be different too. Recently, some studies have investigated whether PAH medications could be used in HFpEF patients, but so far, the results are not encouraging. Professor Ghio concluded by stating that this should not daunt our work but rather boost us to continue investigating PH-LHD physiopathology, using registries as tools.
GROUP 3 PH - Mechanics & Mechanisms of PH in diffuse lung diseases
by Paul Corris
Professor Corris discussed the mechanisms that lead to the development of PH in diffuse lung diseases. He underlined the role of hypoxia inducing hypertrophy and the narrowing of the pulmonary vascular lumen. Some studies showed the genomic adaptation to chronic hypoxic exposures in humans at high altitude. Besides hypoxia, other mechanisms are represented by:
- Vascular restriction/obliteration/apoptosis (in Emphysema /ILD/CFà Thorax 1975 30:285-292)
- Direct vascular remodelling (Inflammatory/fibrotic mediators/smoke)
- Angiogenesis vs angiostasis (especially in ILD)
- Mechanisms specific to disease (Sarcoidosisà arterial remodelling is very prominent, LAM, vasculitis, LCH)
Professor Corris then presented the novelties on clinical classification concerning Group 3 PH from the World Symposium yield in Nice, 2018. He explained that some patients with chronic lung disease may have higher pulmonary pressures than expected. Indeed, in idiopathic pulmonary fibrosis (IPF) there is no correlation between restriction and PH severity (Chest 2007;131). Also, in COPD there is no correlation between grade of obstruction and PH severity (Chaouat AJRCCM 2005; 172:189-194). On the other side, PaO2 and DLCO correlate with SVO2 and cardiac index, while FEV1 is less correlated to these parameters. COPD tend to be more hypoxic than IPF. Exercise limitation is one of the main problems in this subset, and oxygen desaturation during exercise is independent of lung functional tests.
He pointed out the importance of differentiating between Group 1 vs Group 3 PH, considering:
- Pulmonary function tests
- Ancillary testing
Furthermore, there are different patterns in gene expression between PH-COPD and PH-ILD (Hoffmann AJRCCM 2014)
The take-home messages of his presentation were:
- Though alveolar hypoxia is important, evidence supports other genomic and proteomic mechanisms driving vascular loss/remodelling in selected patients
- Mechanisms may vary according to underlying lung disease
- Selected patients may have a vascular phenotype that mirrors patients with PAH and be responsive to therapy
- Urgent clinical need to identify these patients
- PVRI GoDeep project: to deeply phenotype these patients
What clinical phenotype are we looking for?
by Lucilla Piccari
Dr Piccari started off her presentation by discussing the meaning of “phenotype”, defined as the product of interaction between genes, and between genotypes and the environment (MESH library). She then showed some challenging clinical cases of pulmonary hypertension due to different aetiologies.
Dr Piccari strongly suggested that all the different phenotypes of PH due to lung disease may have valid and yet, different reasons to be studied. PH in idiopathic pulmonary fibrosis (IPF) is frequent, rapidly progressive and affects prognosis (worse compared to idiopathic PAH). PH in chronic obstructive pulmonary disease (COPD) is also frequent and affects prognosis. For IPF the rate of mean PAP increase is 3.8 mmHg per month, while for COPD it is 0.65 per year. Some trials aimed at exploring the role of pulmonary vasodilators in interstitial lung diseases as well as in COPD had quite controversial results. Nevertheless, it should be highlighted that inclusion criteria were heterogeneous among these studies.
The relationship between grade of obstruction or parenchymal destruction, and severity of pulmonary vascular involvement is not necessarily linear, as shown by Kovacs et al. (Am J Respir Crit Care Med 2018). In addition, Dr Piccari underlined the importance of the evaluation of hypoxemia and gas exchange impairment in the assessment of pulmonary vascular involvement in COPD.
Finally, she introduced the SUPPORT project (SUrvey on Pulmonary hyPertensiOn in diffuse RespiraTory disease), a multicentre, observational, retrospective anonymised registry aimed at creating an international database to characterise the clinical phenotype of patients with PH associated to chronic lung disease.
Unmet needs and perspectives
by John Wort
Dr Wort started his presentation by discussing the prevalence and the mortality burden of PH due to chronic respiratory diseases: the terrible survival of these patients identifies an important unmet need in this clinical setting.
Then he focused on the different pathogenetic mechanisms of PH in these conditions, highlighting the role of hypoxia, the possible overlapping with acute and chronic pulmonary embolism, and the presence of comorbidities including obstructive sleep apnea. Current treatment options are oxygen, ventilation, antibiotics and anticoagulant, as specifically needed. Concerning potential use of specific pulmonary vasodilator drugs, he stated that there are very few randomised controlled clinical trials, which are often very small, with heterogeneous populations, any amount of PH, sometimes without hemodynamic assessment, and with controversial results.
Dr Wort also underlined the importance of distinguishing group 3 PH from group 1 PAH with mild coincidental lung disease (using the algorithm proposed during the 2018 World Symposium PH in Nice). Indeed, the presence of co-existing lung disease in idiopathic PAH has a negative impact on prognosis, thus suggesting the importance of lung function evaluation also in patients classified as Group 1 PAH.
Another unmet problem is represented by the need of increasing the understanding of the interaction between lung disease and the pulmonary vascular system. In this regard, international multicentre registries may significantly help, as well as the adoption of a comprehensive-omics approach, especially “radiomics”. Furthermore, promoting basic science might lead us to better characterise mechanisms underpinning vascular remodelling in Group 3 PH.
Future trials should be represented by registries focused on collecting outcomes like morbidity and mortality rates, exercise capacity and quality of life. They should include severe PH patients, and so the next step might be represented by designing treatment trials.
GROUP 4 PH - PEA vs BPA
PRO by Andrea Maria D’Armini
Pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) are two different treatments for two different phenotypes of the same disease: chronic thromboembolic pulmonary hypertension (CTEPH).
Professor D’Armini started his presentation by highlighting that, according the ESC/ERS guidelines, PEA is the gold standard for the treatment of CTEPH in patients who are technically operable and who have an acceptable risk/benefit ratio. The definition of “technically operable” and the characteristics of the “optimal candidate” have deeply changed in the latest years and may be different from centre to centre. From a technical standpoint, the procedure largely ameliorated over time, thanks to the improvement in knowledge, surgical techniques and instruments, as well as to the advances in anaesthesia, leading to less restrictive criteria for surgery eligibility.
Professor D’Armini showed data from his programme at the San Matteo Hospital of Pavia (one of the 5 main world PEA centres) and described the Pavia surgical protocol, which is slightly different in comparison to the original San Diego protocol, with intermittent short periods of circulatory arrests followed by short re-perfusion periods, without aortic clamp and cardioplegia, and with moderate hypothermia. Over the years, more and more patients have been suitable for surgery and, nowadays, PEA can cure patients also with distal pulmonary vascular involvement.
CON by Arne Kristian Andreassen
On the other hand, Professor Andreassen showed that BPA, a more recent technique, is a valid option for those patients who are not eligible for PEA, because of comorbidity, which would represent a burden for anaesthesia, or because of the characteristics of the disease, such as thrombosis that are localised in branches too distal to be reached with PEA. This procedure has been largely investigated, especially in Japan, and the number of BPA case reports and clinical studies have significantly increased in the last 10 years. ESC/ERS guidelines reserve this procedure for patients who are technically non-operable, who have non-acceptable risk/benefit ratio or have persistent symptomatic PH after PEA. BPA should be performed only in expert centres.
Professor Andreassen also described the BPA procedure in detail, discussing its potential complications. He then showed his data on BPA from the Norwegian Registry. Over the years, 54 patients have been treated with BPA, obtaining a significant improvement in haemodynamics, exercise, echocardiographic and clinical parameters, as well as symptoms and biomarkers.
Finally, Professor Andreassen showed the study design of the RACE (Riociguat versus balloon pulmonary angioplasty in non-operable chronic thromboembolic pulmonary hypertension) study, now in the recruiting phase, that is comparing medical therapy with Riociguat to BPA in non-operable, CTEPH patients eligible for both treatments.