Due to substantial progress in the early diagnosis and treatment of children born with congenital heart disease (CHD), mortality rates in this population have declined significantly. It is estimated that more than 90% of pediatric patients with CHD now survive into adulthood.1 Among the reported 1.4 million adults with CHD in the United States, pulmonary arterial hypertension (PAH) occurs in approximately 10% of cases.2,3

PAH associated with CHD (PAH-CHD) is linked to significant reductions in survival and quality of life, especially for patients progressing to Eisenmenger syndrome, the most severe phenotype of PAH-CHD. Treatment requires lifelong management in multidisciplinary specialty centers with expertise in PAH-CHD. Advances in treatment for pediatric CHD have led to a reduction in the number of patients who ultimately develop Eisenmenger syndrome, and the management of remaining cases has improved with the use of disease-targeting therapies.3

However, there are numerous remaining gaps in PAH-CHD research and treatment overall, particularly in the area of PAH associated with systemic to pulmonary shunts.3 With greater numbers of CHD patients reaching adulthood and thus facing an increased risk of developing PAH, there is a critical need for effective treatment options for the various forms of PAH-CHD.1

We interviewed the following experts to learn about recent advances and ongoing gaps pertaining to this heterogenous disease: Stephen Chan, MD, PhD, FAHA, professor of medicine in the division of cardiology, director of the Vascular Medicine Institute, and director of the Center for Pulmonary Vascular Biology and Medicine at the University of Pittsburgh School of Medicine and UPMC in Pennsylvania; and Anushree Agarwal, MD, FACC, assistant professor of medicine in the division of cardiology at the University of California San Francisco (UCSF) School of Medicine and cardiologist at the UCSF Adult Congenital Cardiology Clinic.


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What are some of the most notable recent developments for the treatment of PAH-CHD?

Dr Chan: There is almost a desperate need to gather more insights into the cause and development of PAH in CHD. Historically and even now, this has been a slow process with few scientists and clinicians dedicated to research in this field. As a result, changes in the management strategies of PAH with CHD have also moved very slowly.

There are answers on the horizon, though. On one hand, there are new technologies in research that are being applied to understand why CHD can promote PAH. Increased pressure and flow in the pulmonary circulation has historically been assumed to be the cause, but only now are there new discovery platforms being developed — computational modeling of flow through the pulmonary vessels, and synthetic and bioengineering platforms to model flow, among several — that will more rapidly advance our understanding of these complex systems in the body.

Additionally, there is more appreciation that complex genetic and chromosomal abnormalities, independent of pressure and flow in the pulmonary circulation, are primary causes of PAH with CHD.4,5 The advent of whole genome sequencing and ways to edit the genome with CRISPR/Cas9 technology has opened up numerous possibilities to explore these points in greater depth.

Because those fundamental insights into this disease are still pending, clinical management of PAH-CHD has been slower to advance. Historically, a big decision point is whether a surgical intervention should be pursued in CHD to prevent PAH, and this often is very time-dependent. Now there exist targeted drugs that we use in other types of PAH that have been applied for use in PAH in CHD which theoretically may be able to extend the time when surgery could be pursued before it is “too late.” But we need more clinical data to be sure that all of these drugs are effective for PAH-CHD and should be used for this purpose.

There are also other patients with CHD who develop PAH later in life or who never had the opportunity for surgery in the first place. These patients are often considered for targeted drug therapy in the hope that these will be effective. In the near future, we hope that the next generation of PAH drugs that are targeting the vessel remodeling aspects of this disease will also be tested and found to be effective for PAH-CHD.

Dr Agarwal: The most notable recent developments have primarily been related to the increase in the availability of disease-modifying therapies and broadening of indications for the use of these therapies. A couple of examples of this are the “treat-to-repair” strategy and the ability to use oral agents. 

The treat-to-repair strategy is increasingly being used and has revolutionized the outcomes of patients born with shunts such as atrial septal defect, ventricular septal defect, or patent ductus arteriosus. This strategy involves the use of PAH therapies to bring pulmonary vascular resistance into a range where repair of the shunts can be considered. There is emerging data indicating that these strategies are effective and safe at least in the short-term, although long-term follow-up data is still lacking.

We, at UCSF, have been using the treat-to-repair strategy with a lot of success and have closed the shunts in a number of patients after treating them with pulmonary vasodilators. One such patient at UCSF has successfully been taken off pulmonary vasodilator therapy after repairing her shunt and is now tolerating pregnancy quite well. This was a long process and took about 4 to 5 years to help her through it, but is quite rewarding to see her clinical outcome.  

Regarding oral PAH therapies targeting the nitric oxide pathway and the endothelin pathway, which have been available for some time, there are quite a lot of patients who have significant residual PAH or symptoms on these agents. Epoprostenol, an intravenous agent, that targets the prostanoid pathway, is used in patients with repaired CHD, but the use of central lines exposes the patient to sepsis as well as paradoxical embolism in those with unrepaired defects.

Therefore, oral or inhaled therapies are preferred over intravenous therapies in CHD.

Inhaled therapy has its own challenges with compliance and inconvenience of administration, limiting its use in patients with CHD. Recent approval of an oral prostacyclin receptor agonist, selexipag, is a promising first step.6 Although the role for this promising therapy is yet to be clarified in CHD, we have many patients in whom we have been able to offer this agent, obviating the use of inhaled or intravenous therapies.   

There have also been improvements in the ability to provide minimally invasive treatment options such as ductal stenting for persistent ductus arteriosus, surgical Potts shunt, and atrial septostomy — percutaneously or surgically — all of which are emerging promising approaches if performed by experienced operators.  

What are some of the most significant remaining gaps in terms of treatment or otherwise?

Dr Chan: Simply put, we need better drugs for PAH in general and certainly for PAH-CHD. While we think the current vasodilators extend the time to worsening of disease, they are not curative and do not reverse disease. We need more of a fundamental understanding of the processes that drive disease progression. This is particularly notable in the case of numerous adult patients with CHD who develop PAH later in life even after surgical correction of CHD. We have very little understanding as to why these patients even develop PAH if their CHD has been corrected. We need more participation of patients with PAH-CHD in clinical trials, and we need more trials directed toward this specialized and complex patient set.

Dr Agarwal: Most of the existing clinical trials evaluating the safety and efficacy of various disease-modifying therapies have usually excluded or underrepresented patients with CHD, hence the congenital cardiologists are left behind with off-label use of most of these therapies. One of the most significant gaps is the lack of evidence regarding safety and efficacy of existing treatments among patients with CHD, especially understanding the differences between various phenotypes within CHD such as those with previously repaired CHD and unrepaired CHD.

Other important gaps include the absence of long-term follow-up data to understand the duration of therapies, and the lack of evidence-based outcome measures specific to patients with CHD to guide the duration and intensity of the therapies. Although 6-minute walk test, WHO functional class, tricuspid annular plane systolic excursion, and N-terminal pro-brain natriuretic peptide are some of the recommended treatment goals, there is lack of evidence-based measures for patients with CHD that might be more relevant.

In addition, many of the patients with PAH-CHD are reaching childbearing age. Pregnancy is contraindicated for women with PAH in current guidelines.7 However, it remains unclear whether existing therapies are safe in pregnancy and whether treatment with these agents during pregnancy could reduce the overall mortality and morbidity risks for women desiring pregnancy. We had a patient at UCSF who got diagnosed with PAH and pregnancy at the same time and refused termination. Using a multidisciplinary approach, she was managed with intravenous agents throughout the pregnancy and labor/delivery. Overall, she had a good outcome, but the data in this area doesn’t exist.   

Currently, what are the key treatment implications for clinicians regarding this topic?

Dr Chan: In the current era, treatment options include surgical correction of CHD if the timing is correct, and the ability to use targeted vasodilators both to extend the time frame of when surgery is feasible and to treat PAH-CHD independent of surgical correction. These are not cures and do not reverse the disease.

Dr Agarwal: Given that patients with CHD are surviving longer — thanks to great advances in pediatric CHD care — the burden of PAH-CHD is significant and will continue to increase. Thankfully, there is considerable promising progress being made in terms of treatment options for PAH in general. There is anecdotal evidence that these approaches can be successfully used in patients with CHD. However, patients with CHD are quite heterogenous, and a “one-size-fits-all” approach usually does not apply to them. The management of PAH-CHD requires a multidisciplinary, individualized approach provided at specialty centers, and hence collaboration with the specialists while caring for these patients would be key.  


What should be the main focus of research in this area?

Dr Chan: There are 2 main areas of need, including fundamental research into the pathogenesis of PAH-CHD. This will require multi-disciplinary work utilizing bioengineering, computational biology, molecular and cellular biology, and physiology platforms to discern the extreme complexity of this type of disease. The second area is clinical testing in this specialized patient population. Historically, we have had very little participation and enrollment, as well as a small number of trials specifically targeting this growing population. Trials should prioritize testing of existing and advancing new drugs in this space for PAH-CHD. Studies should also begin to consider new in vivo imaging platforms to track disease longitudinally and early in the disease process.

Dr Agarwal: Remaining needs include the following: identifying more oral agents to revolutionize the treatment of PAH-CHD; performing clinical trials to investigate the safety and efficacy of agents focused on patients with CHD, and within CHD, presenting data based on the different CHD phenotypes that takes into account the heterogeneity of CHD; research on women of childbearing age; research to build evidence on the appropriate CHD-specific outcome measures to guide PAH treatment; and long-term follow-up data to guide duration of treatment and to facilitate appropriate counseling on prognosis and natural history of the disease while on disease-modifying agents.  

References

  1. van Dissel AC, Mulder BJ, Bouma BJ. The changing landscape of pulmonary arterial hypertension in the adult with congenital heart disease. J Clin Med. 2017;6(4):40.

2.     Gilboa SM, Devine OJ, Kucik JE, et al. Congenital heart defects in the United States. Circulation. 2016;134(2):101-109.

3.     Brida M, Nashat H, Gatzoulis MA. Pulmonary arterial hypertension: closing the gap in congenital heart disease. [Published online ahead of print July 9, 2020.] Curr Opin Pulm Med. doi:10.1097/MCP.0000000000000695

4. Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019;53(1):1801899.

5. Hosokawa S, Vanderpool RR, Ishii T, Nishiyama M, Doi S. What causes pulmonary arterial hypertension in Down syndrome with congenital heart disease? Circ J. 2018;82(6):1513-1514.

6. Coghlan JG, Channick R, Chin K, et al. Targeting the prostacyclin pathway with selexipag in patients with pulmonary arterial hypertension receiving double combination therapy: Insights from the randomized controlled GRIPHON study. Am J Cardiovasc Drugs. 2018;18(1):37-47.

7. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018; 39(34):3165–3241.