It's Classified: The Complexity of Pulmonary Hypertension Associated with Congenital Heart Disease

Patients with pulmonary hypertension associated with congenital heart disease (PH-CHD) are a complex, heterogeneous group with anatomic and hemodynamic considerations that impact treatment and prognosis. It can be challenging to place a patient with PH-CHD into a single World Symposium of PH (WSPH) diagnostic classification¹, affecting representation in clinical trials and registries. With little understanding of the cause and pathophysiology in some subgroups of PH-CHD, definitive evidence for management of PH-CHD is lacking. In this AHA Scientific Statement, Jone and co-authors delineate the various types of PH-CHD, describe current imaging modalities, explain medical and surgical management considerations, highlight disparities in diagnosis and treatment, and identify gaps in knowledge and needs for future research in PH-CHD. This AHA Statement provides a foundation for increased understanding of this complex group with the goal of developing tailored therapies to improve quality of life, exercise performance, and patient survival.

Patients with PH-CHD can fall into four of the five different WSPH classifications – Group 1 pulmonary arterial hypertension (PAH), Group 2 PH due to left heart disease, Group 4 PH with pulmonary artery obstructions, and Group 5 PH with unclear or multifactorial mechanisms including complex and single ventricle CHD. Additionally, patients with PH-CHD, particularly premature infants, may have lung disease which adversely affects the pulmonary vasculature leading to characteristics of Group 3 Lung-disease related PH. The authors stress that patients with PH-CHD may be classified into more than one group or may develop characteristics of a different group over time. Patients with Down syndrome and PH-CHD are particularly challenging to classify as they may have large shunts, left heart diastolic dysfunction, and developmental lung disease.

 Group 1 PAH-CHD may be the most recognized subgroup. However, there are 4 distinct hemodynamic and clinical profiles clearly delineated in the AHA Scientific Statement. The diversity of presentation affects treatment goals and prognosis. In patients with Eisenmenger syndrome (ES), unrepaired, unrestrictive shunts lead to pulmonary arterial damage and severe elevation in pulmonary vascular resistance (PVR), reversal of shunt direction, systemic cyanosis, and multisystemic involvement. Clinical trials of patients with ES have demonstrated improved quality of life and exercise tolerance with oral pharmacotherapy^2,3. The second sub-group of PAH-CHD includes patients with moderate-to-large, unrepaired, left to right intracardiac or inter-arterial shunts with modest elevation in PVR in whom shunt closure is under consideration. It has been proposed that patients with indexed PVR < 4 WU/m² on cardiac catheterization may undergo successful shunt closure while those with indexed PVR > 8 WU/m² are physiologically similar to ES and are unrepairable. Care of patients in the intermediate "grey zone" is challenging and may include a trial of pulmonary vasodilator treatment with re-evaluation of hemodynamics prior to possible repair. The implications of these hemodynamic criteria for repair on long term PH and right ventricular (RV) function are not known. In fact, patients with persistent or recurrent PAH following surgical repair of CHD comprise a third group of PAH-CHD that is associated with poor prognosis. Finally, some patients with PAH have small, coincidental, often pre-tricuspid shunts that would not be expected to result in the severity of PAH manifested. Patient survival is similar to idiopathic PAH.

 While historically considered rare in children, Group 2 PH due to left heart disease is increasingly recognized in children with congenital or acquired obstruction to pulmonary venous egress (pulmonary vein stenosis, cor triatriatum, congenital mitral valve disease) or left ventricular (LV) diastolic dysfunction seen in various forms of left heart hypoplasia with biventricular circulation. This group is challenging to manage as isolated post-capillary PH in which pulmonary vasodilator use is potentially harmful may evolve into combined pre- and post-capillary PH with secondary arterial disease that can sometimes be treated with pulmonary vasodilators in an experienced pediatric PH center. Patients with CHD and Group 4 PH due to pulmonary artery obstructions have not been studied for the presence of distal pulmonary arterial disease or response to therapy. Finally, patients with PH related to single ventricle CHD are characterized as Group 5 PH with unclear or multifactorial mechanisms. The WSPH definition of PH (mean pulmonary artery pressure greater than 20 mm Hg) is not relevant in this population, but instead "pulmonary hypertensive vascular disease" is defined as a transpulmonary gradient > 6 mm Hg and an indexed PVR > 3 WU/m^{2 4,5}. While low PVR is essential to forward flow in cavopulmonary anastomoses, there are scarce data on the mechanisms and pathophysiology of PH in single ventricle CHD. Sildenafil is commonly used as first line therapy in these patients, but some studies suggest an important role for endothelin in this circulation and increased study of endothelin receptor antagonists is warranted^6,7.

 This AHA Scientific Statement stresses that hemodynamic cardiac catheterization with confirmation of elevated PVR should be performed prior to initiating PH therapy in any patient with PH-CHD. Acute vasoreactivity testing may be useful in determining operability in patients with shunts and in risk assessment for those with incidental shunts but with clinical presentations similar to idiopathic PAH. The role of acute vasoreactivity testing in follow-up surveillance of patients with PH-CHD, especially single ventricle CHD, is less clear. However, echocardiography remains the mainstay of follow-up imaging in patients with PH-CHD, with promising developments in cross-sectional imaging on the horizon as well. The authors call for the development of an echo score for patients with PH-CHD that can be incorporated into new risk stratification scores in youth with PH and possibly guide management with fewer lifetime cardiac catheterizations. Echocardiographic assessment of the size and function of the sub-pulmonary RV has dramatically improved in recent years and is prognostic in idiopathic and heritable PAH. Table 3 in the AHA Scientific Statement provides a helpful overview of the quantitative assessment of septal position, hemodynamics, and ventricular systolic and diastolic function in PH. Worse RV size (by RV/LV ratio), septal position (by LV eccentricity index), and RV systolic function (by tricuspid annular plane systolic excursion, RV fractional area change, RV strain, among others) correlate with disease progression and worse survival in other forms of PAH^8-10. The significance of these parameters should be tested in subgroups and various lesions with PH-CHD to identify high risk patients likely to benefit from targeted therapy.

 Prognosis of PH patients varies widely by classification and by PH-CHD subgroup. This AHA Scientific Statement highlights significant disparities in socioeconomic status, access to care, complete repair of CHD, availability of medications, access to upfront combination therapy, and enrollment in registries and clinical trials that affect early diagnosis and treatment which are critical to survival in PAH. Patients with PH-CHD tend to have better survival than patients with idiopathic PAH, although there are differences by subtype¹¹. Survival is better in patients with ES compared to those with unrepaired shunts who do not develop the characteristics of ES and compared to those with persistent or recurrent PH after repair of CHD. Patients with PAH and coincidental shunt have outcomes similar to idiopathic PAH while those with predominant left to right shunts and high PVR have the best prognosis, an important consideration when debating operability and considering a "treat and repair" strategy. When considering prognosis, long term data is needed specific to patients with PH-CHD undergoing surgical or catheter-based reverse Potts shunt, a proposed palliative alternative to lung transplantation for patients with RV failure despite maximal pharmacotherapy.

 This AHA Scientific Statement is an important resource for any provider caring for patients with various forms of PH-CHD. Management of these patients requires nuanced appreciation of anatomic and hemodynamic considerations common to subtypes of patients. Quantitative echocardiographic assessment of RV size and function is critical to identifying high risk patients in need of aggressive therapy. As data are clearly lacking on the underlying causes and pathophysiology within various subgroups, the authors challenge investigators to study PH-CHD so that targeted drug development and effective treatment strategies may lead to better outcomes in this growing group of patients.