PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

PH Roundtable: Genetics and Pulmonary Hypertension

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Pulmonary Hypertension: From an Orphan Disease to a Public Health Problem

With the market for direct-to-consumer genetic testing expanding rapidly, clinicians are playing catch-up.

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

The study of rare diseases is limited by just that, their infrequency. Pulmonary arterial hypertension (PAH), for example, has a prevalence of 15 cases per million.1 Although there has been an explosion in knowledge of and therapies for this life-threatening disease over the past decade, most of our insight is based on small studies. The first therapy that was approved by the Food and Drug Administration in 1995, intravenous epoprostenol, was based on the results of an 81-patient trial.2 The most recently approved therapy, inhaled treprostinil, in 2009, was based on the results of a 235-patient trial.3 Similarly, our understanding of the natural history of this disease is based on small observational series. Articles see pp 156 and 164 To further our comprehension of rare diseases, we often turn to “registries,” constructed as multicenter cohorts of patients who have the disease with longitudinal follow-up. Despite the inherent limitations of their observational and uncontrolled nature, which also represent strengths, these cohorts are useful to describe and compare patient characteristics, practice patterns, and outcomes. Observations from such registries can generate hypotheses that subsequently form the basis of further studies. Lastly, such cohorts facilitate the study of the prognostic profile of the disease via the derivation and validation of clinical prediction tools. In this issue of Circulation , data from the 2 of the most important present-day registries in PAH give us the opportunity to better understand the prognosis of PAH, its determinants, and outcomes in the current treatment era. Humbert and colleagues4 share data from the French National Registry, in which 354 consecutive idiopathic, heritable, and anorexigen-associated patients with PAH were enrolled from October 2002 to October 2003. They report 1-, 2-, and 3-year survival rates of 82.9%, 67.1%, and 58.2%, respectively. Sadly, despite the many advances in …

Chest CT findings in idiopathic and heritable pediatric pulmonary arterial hypertension

0462: Chest CT findings in idiopathic and heritable pediatric pulmonary arterial hypertension

Prevalence and Prognostic Value of Left Ventricular Diastolic Dysfunction in Idiopathic and Heritable Pulmonary Arterial Hypertension

Although previous studies have demonstrated that paediatric pulmonary arterial hypertension remains distinct from that in adults, there are limited studies evaluating a direct comparison between children and adults. The aim of this head-to-head comparison study was to compare the gender, haemodynamic parameters, and prognosis between paediatric and adult pulmonary arterial hypertension. We retrospectively assessed the clinical differences in 40 childhood-onset (under 20 years old) patients and 40 adult-onset patients with idiopathic and heritable pulmonary arterial hypertension who were followed up at two centres. There was no female predominance among patients with childhood-onset pulmonary arterial hypertension (child female: 42.5%, adult female: 80%). The percent of New York Heart Association functional class IV in adult-onset pulmonary arterial hypertension tended to be higher than those in childhood-onset pulmonary arterial hypertension (22.5 and 10%, respectively), although children had worse haemodynamic parameters at diagnosis (mean pulmonary artery pressure (children versus adults); median 65 mmHg versus 49 mmHg, p < 0.001). There was no significant difference in the event-free survival rate between the two groups (95% vs. 85%) during the follow-up period (median, 96 months; range, 1-120 months). Although paediatric pulmonary arterial hypertension patients had worse haemodynamic parameters at diagnosis than adults, children survived as long as adults with appropriate therapeutic strategies.

Effectiveness of Transition from Intravenous Epoprostenol to Oral/Inhaled Targeted Pulmonary Arterial Hypertension Therapy in Pediatric Idiopathic and Familial Pulmonary Arterial Hypertension

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.

Pathogenic genetic variants have been found in patients with different forms of pulmonary arterial hypertension (PAH). Our aim was to define the genetic background of patients with idiopathic PAH (IPAH), heritable PAH (HPAH), pulmonary veno-occlusive disease (PVOD) and PAH associated with congenital heart disease (PAH-CHD); both in adult and pediatric age. REHAP and REHIPED are Spanish, voluntary, multicenter registries that include patients with PAH. REHAP started in 2007 and includes patients over 18 years of age. REHIPED started in 2009 and collects patients between 2 months and 18 years of age. Patients with IPAH, HPAH, PVOD and PAH-CHD who have undergone a genetic testing were included. 413 adults and 122 children were analyzed. From 2011, Sanger sequencing and multiplex ligation-dependent probe amplification were used to detect genetic variants in the BMPR2, TBX4, and KCNK3 genes. Since 2014, a next generation sequencing (NGS) panel of 21 genes was applied. In 2017 this panel was expanded to cover 35 genes, and in 2019, it was expanded to 37 genes. Since 2020, whole-exome sequencing has been applied for the previously followed-up patients without known pathogenic/likely pathogenic (P/LP) genetic variants, and for each incident case. There was a statistically significant difference (p 0.031) in the etiologies among adults and children. The etiologies in adults were 242 (59%) IPAH, 25 (6%) HPAH, 83 (20%) PAH-CHD, 63 (15%) PVOD. The etiologies in children were 66 (54%) IPAH, 8 (7%) HPAH, 38 (31%) PAH-CHD, and 10 (8%) PVOD. The genetic testing had a variant in 121 (29%) adults (56% pathogenic, 9% likely pathogenic, 32% VUS) and 63 (52%) children (65% pathogenic, 16% LP, 19% VUS) (adults vs children p &amp;lt; 0.001). BMPR2 was the most frequent variant in both populations, followed by EIF2AK4. Patients with HAPH and PVOD are more likely to have a genetic variant, while PAH-CHD are the less likely to have one; both in adults and children (p&amp;lt;0.001). The etiology was reclassified after the genetic testing in 13% adults and 19% children (p 0.08); including 6 adults and 4 children initially classified as IPAH and then diagnosed of PVOD when a P/LP variant was found in EIF2AK4. Also, 5 children were initially diagnosed as IPAH and then reclassified as multisystemic disorders (4 NFU1 and 1 MECP2) In conclusion, a significant number of patients with PAH have a variant in genetic testing, especially if they are diagnosed in pediatric age. BMPR2 is the most frequent variant in our cohort, followed by EIF2AK4. Knowing the genetic background of our patients enables a better classification and understanding of the disease. This is especially important in patients initially diagnosed of PAHI who are then classified as PVOD. Also, knowing the genetic background may help develop new treatments in the future.

Right Atrial Conduit Phase Emptying Predicts Risk of Adverse Events in Pediatric Pulmonary Arterial Hypertension

Syncope is more common in children with idiopathic pulmonary arterial hypertension (PAH) than in adults with PAH. Although syncope is associated with a poor prognosis in adult PAH, the clinical effects of syncopal events on disease severity and outcome in children have not been carefully investigated. This study assessed the prevalence of syncope in pediatric PAH and examined its clinical, hemodynamic, and prognostic importance. This retrospective study assessed clinical data, including syncope status, from 78 children (37 girls) with idiopathic and heritable PAH (median age at diagnosis, 11years). Patients were classified as syncopal or non-syncopal, and clinical data from the two groups were compared. The primary outcome was a composite of lung transplantation and cardiac mortality. Overall, 31 (38%) children had a history of syncope at presentation. Median age at diagnosis, sex ratio, brain natriuretic peptide level, and 6-min walk distance at diagnosis did not differ between groups. The hemodynamic parameters of initial right heart catheterization were similar between the syncope and non-syncope group (mean pulmonary artery pressure, 67 versus 71mm Hg; cardiac index, 2.9 versus 2.9l/min/m2, respectively). There was not significantly difference in event-free survival rate between two groups. Although syncopal events are common in children with PAH, our findings suggest that syncope may not be correlated with disease severity or outcome in pediatric PAH.