The 6th World Symposium on Pulmonary Hypertension: what’s old is new

Novel genes associated with pulmonary arterial hypertension

Since its discovery in 2000⁴, BMPR2 mutations remain the most common genetic cause of PAH, accounting for about 80% of HPAH and about 20% of IPAH. Besides BMPR2, other transforming growth factor beta (TGF-β) superfamily genes, including ALK1/ACVRL1 (a heterodimeric partner of BMPR2), BMP9 (a BMPR2 ligand), ENG (a co-receptor for BMPR2 signaling), and SMAD1, 4, and 9 (downstream BMP signaling molecules), have been linked to both HPAH and IPAH⁵. In the last 5 years, next-generation sequencing technologies have been applied to genetic discovery in patient populations with IPAH, HPAH, and drug-induced PAH. For example, whole exome sequencing (WES) in BMPR2-negative HPAH patients led to the discovery of two novel genes: CAV1 (involved in BMPR2 membrane localization and signaling)⁶ and KCNK3 (a potassium channel that regulates resting membrane potential)⁷. More recently, a WES screen of pediatric patients with HPAH revealed that, in addition to BMPR2, the most common mutation in this patient population was in TBX4, a gene linked to small patella syndrome⁸. Besides WES, whole genome sequencing (WGS) has now been used to characterize novel high-risk gene variants in large patient populations. A WGS study of 1048 patients with PAH by Gräf and colleagues⁹ screened and found novel mutations in GDF2 (which codes for BMP9) and identified ATP13A3, AQP1, and SOX17¹⁰ as novel gene candidates, although the specific pathogenic mechanism of these in PAH remains to be determined.

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are severe forms of WHO group 1 PH with a rapidly progressive clinical course and poor response to therapy. In 2014, the first of two scientific groups reported that mutations in EIF2AK4 (a kinase involved in amino acid metabolism) were associated with both PVOD and PCH^11,12. In contrast to BMPR2 mutations, EIF2AK4 mutations are autosomal recessive and completely penetrant. Detection of EIF2AK4 in a patient with PAH can establish the diagnosis of PVOD/PCH in the appropriate clinical context without necessitating lung biopsy¹².

The 6th WSPH Task Force on Genetics and Genomics has updated the list of gene candidates for PAH to include these new genes and strongly recommends research in understanding how they are linked to PAH pathogenesis and how this information could be used in biomarker discovery and new therapeutics¹³.

Genetic counseling

As WES and WGS become less expensive and more available, the importance of explaining these results and their significance for patients and potential offspring is critical. Given the complexities of the genetic processes underlying HPAH, this only adds nuance to the difficult task of genetic counseling to patients with a family or personal history of HPAH looking to conceive. The psychosocial concerns of genetic screening for a disease for which there is no prevention and no specific cure may weigh heavily on those affected and may cause guilt to those not phenotypically affected or who could pass disease-causing mutations onto children. After discussing the potential benefits of genetic screening (that is, early detection of family members and earlier initiation of therapy when indicated), the 6th WSPH task force recommended that genetic screening be carried out under the guidance of a genetic counselor or clinical geneticist¹³. At this point, a pedigree can be generated to identify relatives at risk, although gene testing or screening should be initiated with affected patients. There are different methods of evaluating the genetics of affected patients. In addition to commercially available diagnostic PAH/PVOD gene panels, WES or WGS may be appropriate for a patient with a negative gene panel and also have important relevance for research. However, it must be stressed that these diagnostic tests should be ordered by a specialist who is trained in genetics and who would assume the responsibility of counseling patients and their families regarding the implications of the test results.

Risk stratification

The clinical status and trajectory of patients with PAH can be defined through the use of multiple validated risk stratification tools. The many available comprehensive risk stratification tools use a combination of parameters that assess clinical, functional, cardiac, and hemodynamic status to assign patients to low-, intermediate-, or high-risk categories. Without delving into the intricacies of the superiority of one validated assessment tool over the other, what is clear is that the baseline use of these tools can predict survival and event-free survival for up to 5 years^25,26 and that, in certain situations, re-classification into a different category at follow-up on the basis of re-scoring can predict outcomes over the next year. Within the mélange of these risk stratification systems, the following parameters appear to have the greatest predictive capability: functional class, six-minute walk distance (6MWD), N-terminal pro-brain natriuretic peptide/brain natriuretic peptide (NT-proBNP/BNP) levels, cardiac index, right atrial pressure, and mixed venous oxygen saturation (SvO₂)^27,28. The guidelines acknowledge that the limitations of these tools include the inability to account for non-modifiable/ill-modifiable risk factors such as age, sex, comorbidities, and additional data available through advanced investigative techniques such as cardiac magnetic resonance and cardiopulmonary exercise testing²⁹. In addition, most of these tools are time-consuming to use and require data points that are not routinely obtained. At present, it is also unclear which parameters define the set of patients with prolonged clinical stability. Use of machine learning and artificial intelligence in future work may assist in developing new, low-bias prediction tools that eliminate some of the above pitfalls with current prediction scores and tools^30,31.

Even as these risk calculators continue to evolve, they remain an important tool in assessing patients in the clinical and research setting while helping to guide management. The task force members recommend that future iterations or refinements also take into consideration accuracy and cost-effectiveness of obtaining included parameters²⁹.

Selected highlights from the updated treatment algorithm

The Dana Point 4th WSPH recommendations from 2008 led to a significant shift in PAH randomized control trial (RCT) design. Multiple recent trials using more clinically meaningful end-points (such as time to clinical worsening, death, or transplant instead of 6MWD) have led to improved confidence in, and adoption of, choices for therapeutic strategy and drug combinations. For all patients with PAH, activity within symptom limits is advised, and recent data affirm the benefits of supervised training across the spectrum of functional impairment²⁹.

Treatment of WHO group 1 PAH by targeting the nitric oxide, endothelin, and prostaglandin pathways has been standard since the 2003 Venice WSPH guidelines; no drugs targeting other pathways have been approved in the interim. The 6th WSPH task force has proposed a revised treatment algorithm (Figure 1) that can be summarized as follows:

Figure 1. Proposed algorithm for treatment of pulmonary arterial hypertension based on 6th World Symposium on Pulmonary Hypertension recommendations.

CCB, calcium channel blocker; ERA, endothelin receptor antagonist; NYHA, New York Heart Association; PDE5i, phosphodiesterase inhibitor.

As data have accumulated from RCTs over the past decade, an increasing emphasis is being placed on upfront combination therapy. Longer-term data are needed to assess the cumulative impact of this strategy on long-term survival. With the drop in the mPAP criterion from 25 to 20 mm Hg, it is imperative that well-designed clinical trials be carried out to determine the impact on long-term outcomes with early intervention.