Genotypes and Phenotypes: Making Progress Toward a Precision Medicine Approach in Pediatric Pulmonary Hypertension

RECENT ADVANCES IN GENETICS OF PEDIATRIC PAH

Identification of novel gene mutations associated with PAH is revealing heritable underpinnings to what was previously classified as idiopathic PAH. It is estimated that 21% of pediatric PAH has a genetic etiology.10 In recent years, a number of genes have been implicated in idiopathic and familial PAH. Mutations in bone morphogenetic protein receptor II (BMPR2) have been identified as the major cause of heritable PAH (~70%) and idiopathic PAH (~20%). Mutations in ACVRL1 and ENG (associated with hereditary hemorrhagic telangiectasia), BMPR1B, SMAD9, CAV1, and KCNK3 are also associated with PAH and mutations in EIF2AK4 have been shown to cause pulmonary capillary hemangiomatosis/pulmonary veno-occlusive disease (PCH/PVOD).11–13 Also, variants in SOX17, a gene encoding a transcription factor involved in vascular development and remodeling, were also recently identified in multiple cohorts of adults and children with heritable, idiopathic, and congenital heart disease–associated PAH.14–16

To determine the role of these genetic variants in pediatric-versus adult-onset PAH, Zhu and colleagues recently compared genetic analysis of adults and children with idiopathic and heritable PAH. They observed similar frequencies of pathogenic mutations in BMPR2 and other known PAH risk genes but found mutations in TBX4 enriched in pediatric-onset PAH.10 TBX4 encodes a transcription factor in the T-box gene family expressed in the heart, limbs, and mesenchyme of the lung and trachea. Mutations or deletions of TBX4 have been associated with small patella syndrome and skeletal abnormalities of the pelvis and lower limbs as well as PAH, which is predominantly pediatric-onset. 17–19 Zhu et al found TBX4 mutation carriers had a 20-year earlier mean age of PAH onset compared with BMPR2 mutation carriers. Within the TBX4 cohort, PAH severity and associated skeletal abnormalities were variable.1018 TBX4 represents the first genetic diagnosis primarily associated with pediatric-onset PAH and may provide insight into mechanisms of disease development in infants and children.

MULTIPLE PHENOTYPES IN CONGENITAL HEART DISEASE–ASSOCIATED PAH

Multiple phenotypes have been established in the congenital heart disease population. The Nice classification highlights 4 main types of PAH associated with congenital heart disease: Eisenmenger syndrome, PAH with left-to-right shunts, PAH with coincidental congenital heart disease (small defects), and postoperative PAH.1 Shunt lesions have long been recognized as contributing to development of PAH. Natural history studies show that unrepaired, large post-tricuspid shunts, such as ventricular septal defects, lead to irreversible PAH in the majority of patients by 2 years of age, informing current practice for early repair of such defects.2021 Patients with pre-tricuspid shunts, such as atrial septal defects, have a much lower risk of developing PAH that tends to occur later in life (6% in one study).22 There are also patients with left-to-right shunts who develop PAH despite appropriate surgical repair, which may suggest a genetic predisposition such as the SOX17 variants described above.16 Similarly, it is well described that a small number (<1%) of patients with transposition of the great arteries develop PAH despite neonatal surgical repair, again suggesting a potential genetic predisposition to developing PAH, although no genetic target has been identified to date.23

Patients with single-ventricle physiology represent another unique subset of children with congenital heart disease who may benefit from a precision medicine approach to diagnosis and treatment. Surgical palliation with cavopulmonary anastomosis (Glenn and Fontan operations) relies on direct drainage of systemic venous return into the pulmonary arteries such that small elevations in pulmonary vascular resistance can impair cardiac output. The pediatric Panama classification recognized that these patients may have pulmonary vascular disease without meeting traditional PAH criteria, and recommended altered criteria of indexed pulmonary vascular resistance >3 indexed Wood units or transpulmonary pressure gradient >6 mm Hg.3 Pulmonary vasodilator therapy has been described in a number of cohorts of single-ventricle patients with some improvement in exercise tolerance and functional class using sildenafil24 and bosentan.25

Dramatic improvement in pulmonary vascular resistance and oxygen saturation was observed in a cohort of single-ventricle patients who received subcutaneous treprostinil (Figure 1) with dramatic clinical improvement in some cases.26 Despite these studies suggesting benefit, optimal PH diagnostic criteria for treatment and approach to pulmonary vasodilator therapy in single-ventricle patients remain somewhat unclear.

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DEVELOPMENTAL BASIS FOR PH ASSOCIATED WITH PREMATURITY AND LUNG DISEASE

While mechanistically different from WHO Group 1 PAH, PH associated with developmental lung disease (WHO Group 3) also results from a reduction in functional vascular area. Instead of the loss of preexisting vessels observed in PAH, developmental PH results from lack of normal growth of the vasculature. This can be due to interrupted development caused by premature birth and subsequent postnatal lung injury and/or from lung hypoplasia secondary to congenital anomalies, such as congenital diaphragmatic hernia.

Advances in medical care have allowed for survival of premature infants at progressively lower gestational ages. While overall survival of infants born at 22–28 weeks has improved in recent years, the incidence of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, has increased.2728 Retrospective cohort studies estimate the incidence of PH to be 50% to 58% in infants with severe BPD, which contributes to significantly increased mortality.2930 Risk factors for PH in this population include lower gestational age and worse BPD, but prediction remains limited. Additional predisposing conditions include small birth weight for gestational age, oligohydramnios, preeclampsia, and postnatal injuries (ie, prolonged duration of mechanical ventilation and oxygen therapy), suggesting that PH susceptibility is related to a complex interplay of genetic, developmental, and environmental factors (Figure 2).3031

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As lung development normally continues until gestation and even beyond, extremely premature infants may be delivered prior to sacculation and alveologenesis, the final phases of lung development that generate functional gas exchange units (alveoli) required for respiration. Understanding of normal lung development is critical both to determine how disruption leads to BPD and PH and to develop therapies directly targeting lung and blood vessel growth. Recent studies have focused specifically on identifying molecular mechanisms driving the saccular and alveolar stages. Generation of normal alveolar structure requires complex interactions between multiple cell lineages, including epithelial, mesenchymal, and endothelial cell types.32 Studies in rodents have shown an important role for Wnt signaling to promote maturation and expansion of alveolar type 2 cells in alveologenesis.33

Studies of BPD pathogenesis demonstrate simplified lung architecture and also immature vasculature, supporting a coordinated codevelopment of the lung airspaces and vasculature.3435 This is supported by prospective clinical studies showing that early diagnosis of PH is associated with a high risk of developing BPD at 36 weeks postmenstrual age.36 Vascular endothelial growth factor (VEGF) is an active angiogenic factor that is also important for distal airspace growth.37 Recently, inhibition of VEGF with a monoclonal antibody for soluble fms-like tyrosine kinase-1 (sFlt-1) preserved lung structure and function and prevented right ventricular (RV) hypertrophy in an experimental rat model of BPD, suggesting that early targeted therapy may provide a novel strategy for BPD prevention.38

Normal vascular development continues postnatally but may be negatively impacted by injury and inflammation from hyperoxia, mechanical ventilation, infection, and aspiration. These insults to the developing lung can decrease alveolar-capillary surface area and worsen PH.39 Current therapies focus on lung protection and growth by limiting mechanical trauma, optimizing lung expansion, and preventing infection and aspiration.40 Little is understood about the response of the developing lung to acute injury postnatally and therefore, targeted therapies are not yet available. Studies using a mouse model of regeneration after influenza-induced lung injury reveal a complex process, mediated by lung progenitor cells. Wnt signaling also appears to be important in mediating response to acute lung injury by alveolar epithelial progenitor cells.41 Detailed understanding of these normal developmental mechanisms and response to injury may be harnessed in the future to develop therapies to promote and restore postnatal alveolar development. Therapies currently being investigated include mesenchymal stem cells and isolated exosomes, which may attenuate lung injury through transfer of VEGF.42–44

DIAGNOSIS AND TREATMENT WITH A PRECISION MEDICINE APPROACH

Advances in Phenotyping Using MRI Biomarkers

A personalized medicine approach to the child with PH will need to include an individualized approach to diagnosis and monitoring. While cardiac catheterization remains the gold standard for hemodynamic assessment and PH diagnosis, there is increasing interest in noninvasive assessments by echocardiography and MRI. These modalities not only alleviate risks associated with invasive procedures and anesthesia but also provide additional assessment of RV function not determined by hemodynamics alone. There is growing interest in use of novel MRI biomarkers, including measures of flow dynamics and RV performance, which may add to hemodynamic assessment of PAH severity and inform prognosis. MRI has some distinct advantages compared to other high-resolution imaging modalities, notably the lack of ionizing radiation and high spatial resolution. For some pediatric patients, use may be limited by long image acquisition time that may necessitate anesthesia in younger or developmentally delayed patients and use of metal-containing medication pumps or devices.

Various MRI parameters may provide unique insight into abnormal vascular function and remodeling in PAH patients. MRI assessment of wall shear stress (ie, the stress applied to the vessel endothelium by flowing blood) is decreased in children with PAH relative to controls and may reflect severity of downstream vascular remodeling.45 Similarly, wave intensity analysis reveals increased pulmonary vascular stiffness in children with PAH relative to controls.46 Increased main pulmonary artery stiffness and decreased wall stress correlate with metrics of RV performance and predict clinical outcomes in a pediatric PAH cohort.47

Much of the focus of recent pediatric studies has been on determining utility of specific MRI biomarkers to predict outcomes. Moledina et al described right ventricular ejection fraction (RVEF) and left ventricular stroke volume index as most strongly associated with survival in a cohort of children with PAH but noted that RV volumes were also significant. They identified specific cutoffs of RVEF <44% and left ventricular stroke volume index <34 mL/m² correlated with decreased 3-year survival.48 In addition, Blalock et al found markedly abnormal RV volumes and RVEF in children with PAH despite normal 6-minute walk distances, suggesting that RV changes may precede clinical symptoms of RV failure in children.49 Novel research measures include MRI assessment of ventricular-vascular coupling (the relationship between vascular and ventricular function) and RV stroke work. The degree of ventricular-vascular decoupling was recently shown to predict RV dysfunction and prognosis.50 Yang et al used computational modeling to include both hemodynamic and MRI data in a calculation of RV stroke work, which outperformed both pulmonary vascular resistance and RVEF in predicting clinical worsening in a cohort of children with PAH.51 In addition to the absolute values, the rate of change of RV stroke work may be particularly helpful to predict clinical worsening in the individual patient (Figure 3). While these studies suggest additive value of MRI in routine clinical assessment, there remains significant variability in current clinical practice. Larger pediatric studies are needed to guide optimal use of specific MRI biomarkers in the clinical setting.

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CONCLUSION

There is increasing recognition of unique genotypic and phenotypic subsets in pediatric PH. We are entering an era of individualized and precision approaches to pediatric PH, as we learn more about the genetic factors and developmental contributors to each of these specific syndromes. It is likely that unique subsets of pediatric PH will have distinct outcomes and require distinctive treatments. Reassessing historical approaches to diagnosis, prognosis, and treatment of pediatric PH will be an essential step as care for children with pulmonary vascular disease transitions to more nuanced, tailored, and individualized patterns of disease management.