Risk Refinement in the “Treat-to-Repair Era”

Corresponding Author

Pulmonary arterial hypertension (PAH) has been reported to occur in up to 35% of patients with unrepaired atrial septal defects (ASDs) and carries an increased risk of morbidity and mortality.¹ Within this cohort of congenital heart disease (CHD)-associated PAH (CHD-PAH), different international societies have classified 4 different subgroups.² Two of these 4, Eisenmenger’s syndrome (type 1) and those with large systemic-to-pulmonary shunts (type 2) have improved survival compared with other noncongenital forms of PAH.³ There has been a particular interest in the study of the latter given the increasingly recognized response to PAH therapies and benefit to late-stage closure of large ASD shunts that were previously thought to be unrepairable.

In this issue of JACC Case Reports, Cazeiro et al⁴ describe a case of type 2 CHD-PAH in a young man who presented with progressive dyspnea on exertion over 10 months and was found to have a large unrepaired ASD with evidence of left-to-right shunting, severe right ventricular dilation and dysfunction, and invasive hemodynamics demonstrating a Qp:Qs of 1.6 and pulmonary vascular resistance (PVR) of 8.56 Wood Units (WU). The clinical team pursued genetic testing in an attempt to identify underlying genetic contributions to the development of pulmonary vascular disease which may result in PVR out of proportion to the degree of shunting, and subsequent increased risk to closure. The patient was placed on dual PAH-targeted therapy and after 4 months of treatment, repeat invasive hemodynamics demonstrated a reduction in PVR to 6.39 WU. Thereafter, fenestrated surgical ASD closure was successfully performed under multidisciplinary guidance and 6 months post-closure, the patient’s PVR showed a further reduction to 3.5 WU.⁴

This case report highlights several salient issues with respect to contemporary management of type 2 CHD-PAH. First, the PVR cutoffs for what is considered “repairable” have increased over the past decade to reflect evidence that patients with longstanding left-to-right intracardiac shunts and initially prohibitively high PVRs can have a robust response to pulmonary vasodilator therapy, and that those who do can be successfully treated with ASD closures, the so-called “treat-to-repair” strategy.¹ Second, despite the increasing tolerance of higher PVRs for ASD closure in patients, there still remains uncertainty about specific target PVRs for closure and also duration of PAH treatment pre- and post-closure. This uncertainty is due to the lack of randomized control trials and also limited follow-up in patients with CHD-PAH post ASD closure, given the relative nascence of the “treat-to-repair” era. Third, as a reflection of the aforementioned uncertainty, international guidelines differ with respect to the strength of their recommendations; notably, the American guidelines assign a IIa recommendation for closure of ASDs with initial PVR of 5 to 8 WU that can be brought down to ≤5 WU with PAH therapy, whereas the European guidelines assign a more conservative IIb recommendation.^5,6 The more liberal American guidelines may be in part due to previous guideline-directed practice patterns and empirical data; the American guidelines previously used ratios of pulmonary to systemic pressures and resistances to guide closure rather than absolute PVR cutoffs (and thus indirectly allowing for closure at higher PVRs) and did not adopt the 2018 World Symposium lowered threshold for pulmonary hypertension until its latest iteration in 2025.⁷

Future directions in treatment of CHD-PAH include refinement of intermediate-risk stratification, which applies to most patients with unrepaired ASDs who are considered for closure in the “gray zone.” Invasive hemodynamics are necessary but insufficient in characterizing patients’ individual risk with respect to shunt closure; as often noted, it is the right ventricular adaptation to pulmonary afterload that portends a more or less favorable outcome in CHD-PAH rather than the numbers alone. Cazeiro et al⁴ perceptively trended the tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio on echocardiogram as a reflection of this principle and the importance of understanding ventriculo-arterial coupling in CHD-PAH, which raises the question of additional noninvasive imaging parameters that may be used for risk stratification.⁸ The utility of genetic testing is also highlighted in the most recent 2022 European Pulmonary Hypertension guidelines, given the potential to identify and reclassify patients with CHD-PAH as having heritable forms of PAH. Several genes as noted in the case report (BMPR2, SOX17, and TBX4) have been identified from biospecimen collection across Europe and associated with worse clinical course and response to treatment; these genes are now targets of emerging therapies on a molecular level.⁹ Nevertheless, genetic testing is not routinely performed in non-European countries in part because of concerns about the generalizability of genetic testing in populations with low European ancestry representation, and further study is needed to characterize the full spectrum of genomic variation involved in heritable PAH risk. Finally, as mentioned previously, target PVRs for closure and duration of PAH therapy pre- and post-closure, in addition to fine tuning risk stratification, will become an important point for future study given that the lifetime incidence of pulmonary hypertension post-closure exceeds 15% regardless of age at time of closure.¹⁰

With more time and further longitudinal data in the “treat-to-repair” era, additional insights into the management of CHD-PAH will allow for more precise risk stratification, patient selection, and treatment of this unique cohort of patients.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.