Atrial septal defects (ASD) are amongst the most common congenital heart defects. A large ASD causes a left to right shunt resulting in right ventricular (RV) dilation from volume overload. About 4% of the patients with ASD develop pulmonary arterial hypertension.¹ Development of pulmonary arterial hypertension (PAH) subjects the RV to additional pressure overload resulting in further dilation, hypertrophy and reduction or reversal of the shunt. In the setting of significant pulmonary vascular disease (PVD), the ASD functions as a “pop-off” mechanism to allow right-to-left shunt in certain circumstances such as increased adrenergic states or pulmonary hypertensive crises. Therefore, closure of ASD in presence of significant untreated PVD can be detrimental.

The medical management of PAH with pulmonary vasodilator therapy leads to improvement in pulmonary vascular resistance (PVR) and reduction in pulmonary artery pressures.  Use of these medications results in improvement in survival, morbidity and quality of life.² The beneficial effects of pulmonary vasodilator have led to a renewed interest in closure of ASD after medical treatment or the so-called “treat and repair” approach. It has been postulated that reduction of PVR from medical treatment of PAH leads to increase in left-to-right and further RV dilation and volume overload. A subsequent closure of ASD with a fenestrated or a non-fenestrated device may lead to reduction or elimination of left to right shunt and lead to more favorable remodeling. Several case series utilizing this approach have been reported.^3-4 However, these case series have several limitations such as variation in PAH medication regimen, time between initiation of medical treatment and closure of ASD, criteria for closure, presence or absence of fenestration in closure device and duration of follow up. Therefore, an optimal management strategy for ASD in setting of PAH is controversial. Specific examples of unanswered questions are:

• What are the clinical and hemodynamic characteristics of patients whose PVD will respond favorably to pulmonary vasodilator medications to enable subsequent ASD closure?
• What is the most effective initial regimen? When and how should the medical therapy be escalated?
• What is a suitable interval for monitoring or repeat cardiac catheterization?
• What hemodynamic parameters on therapy should be considered to make a decision about ASD closure?
• At what time after initiation of pulmonary vasodilator therapy should the patients be deemed not suitable for intervention if their hemodynamic parameters by cardiac catheterization do not improve?
• What closure devices are best: fenestrated or non-fenestrated? If fenestrated, what should be size of fenestration?What are the long-term patency rates?
• What are the short- and medium-term outcomes of patients undergoing treat and repair?
• What are the long-term outcomes? Does the pulmonary vascular disease improve, stabilize or worsen over time after ASD closure? How long do patients require medical therapy after closure?

The standardized approach to management by Yan et. al.,⁵ combining the use of targeted medical therapy and flow limiting fenestrated atrial septal occluder device addresses some of the limitations of the earlier studies and addresses some of the current gaps in the literature.⁵ Therefore, it is an important contribution to the “treat and repair” strategy for ASD closure. In this single center study from China, adult patients with ASD with systolic PA pressures >/=70 and PVR >/= 5 wood units were initiated on fixed dose combination regimen of Ambrisentan (5 mg) and Tadalafil (20 mg). After 3 months of medical therapy, 56 patients underwent ASD closure with a custom-made fenestrated closure device if cardiac catheterization showed Qp/Qs >/= 1:5.  Of these patients, 95% had systemic arterial oxygen saturation of more than 90% or Qp/Qs greater than 1 at baseline. After 3 months of pulmonary vasodilator therapy, the median baseline systolic PA pressure declined from 86 mmHg (IQR: 75.5-95) to 72 mmHg (IQR: 66-80.5) just prior to ASD closure.  Similarly, the PVR declined from 8.6 Wood units (IQR: 7-11) to 4.7 Wood units (IQR: 3.6-5.5).  Remarkably, only one patient had a Qp/Qs < 1:5 after treatment and was excluded from analysis. Significant improvement in exercise was also noted with 3 months of medical therapy alone. This improvement in exercise occurred at the expense of increased RV volumes from increased left-to-right shunt as noted by echocardiography. After a median of 10 months follow-up, partial ASD closure resulted in additional improvement in exercise capacity and reduction in pulmonary arterial pressures. Reduced left to right shunt was noted in all except three patients who had a bidirectional shunt. Consequently, a more favorable ventricular remodeling occurred in form of reduced RV volumes and increased left ventricular volume. The authors intended to repeat right heart catheterization one year after partial closure of ASD. However, the long-term follow up was limited as only 24 patients had a follow-up for more than a year and repeat catheterization was done only in 19 patients after a year. stained favorable hemodynamics were noted in this small group. There were 8 of 19 patients who were noted to have normal pulmonary artery pressures. When pulmonary vasodilators were discontinued in these patients, five developed pulmonary hypertension again requiring restitution of therapy. 

There are several implications of this study. It appears that in the short to medium term, “treat and repair” strategy using a fenestrated device produced favorable results for ASD patients who have elevated pulmonary pressures and resistances but with resting oxygen saturations of more than 90%. Remarkably, it took only 3 months of dual combination PAH therapy to achieve hemodynamics suitable for closure of ASD. This is in contrast to other studies using dual PAH therapy in which the treatment duration ranged from 9 months to 1.8 years before ASD closure was achieved.^3,6 However, in these studies, the decision to perform a cardiac catheterization was often at the discretion of the treating physician rather than driven by a study protocol. While there are no current guidelines on when the invasive cardiac hemodynamics should be reevaluated, the current study suggests an earlier assessment. Whether medication uptitration, use of triple therapy or prolonged administration of PAH therapy will eventually help more patients undergo ASD closure cannot be commented upon. Finally, it is likely that the majority of the patients will require PAH therapy for prolonged periods of time after ASD closure.

A comparison of recommendations (Table 1) from major international guidelines shows that both guidelines recommend consultation with adult congenital heart disease and pulmonary hypertension experts for management of ASD associated PAH.^7,8 However, the European Society of Cardiology (ESC) guidelines are more explicit in recommending closure of ASD with a fenestrated device in patients in whom the PVR improves to less than 5WU and Qp/Qs exceeds 1.5 on pulmonary vasodilator therapy. This might be due to the fact that custom-made fenestrated devices are more widely available in Europe than in the United States (US). In the study by Yan et. al.,⁵ about 25% of the patients had PVR >5.5 WU at the time of ASD closure. Therefore, it is possible that as more data accumulates, the cutoffs recommended in the ESC guidelines may change in future.

Table 1: Comparison of recommendations for closure of ASD by international guidelines.

Recommendation	ESC 2020	ACC/AHA 2018
Close	RV overload and PVR < 3WU and no LV disease (I)	Symptomatic with Qp/Qs ≥ 1.5 and PA pressure < 50% of systemic pressure and PVR < 1/3rd of systemic resistance (I)
Consider closure	PVR 3-5 WU and Qp/Qs > 1.5 (IIa) Fenestrated ASD closure in patients with PVR >5 WU that improves to <5 WU on PAH therapy with Qp/Qs > 1.5 (IIb)	Asymptomatic with Qp/Qs ≥ 1.5 and PA systolic pressure < 50% of systemic systolic pressure and PVR < 1/3rd of systemic resistance (IIa) Qp/Qs ≥ 1.5:1, PA systolic pressure is >50% systemic arterial systolic pressure, and/or PVR > 1/3rd of systemic vascular resistance (IIb) after consultation with ACHD/PH experts
No closure	Eisenmenger physiology or PVR >5 WU despite PAH therapy or PAH with exercise desaturation	PA systolic pressure > 2/3rd systemic systolic pressure, pulmonary vascular resistance > 2/3rd systemic, and/or a net right-to-left shunt

Despite supportive short- to medium-term data, the long-term natural history of pulmonary vascular disease (PVD) in the patients treated with ‘treat and repair’ remains unknown. While custom-made fenestrated closure devices are not available in US, we anticipate the availability of fenestrated devices in Europe and Asia and its endorsement in the ESC guidelines may lead to more widespread use and provide us more safety and outcomes data. Hopefully, this will reduce the need for MacGyvered fenestrated devices, which may have higher risk of spontaneous closure.⁹

Given the above uncertainties, the decision to follow a ‘treat and repair’ or ‘medical treatment alone’ approach should be made on an individual basis. We agree that such patients should undergo comprehensive evaluation in a specialist Adult Congenital Heart Disease-Pulmonary Hypertension center as recommended by the guidelines. A meticulous approach is needed towards appropriate patient selection. Patients chosen to undergo the procedure should be appropriately consented and counseled.

References

1. Vogel M, Berger F, Kramer A, Alexi-Meshkishvili V, Lange PE. Incidence of secondary pulmonary hypertension in adults with atrial septal or sinus venosus defects. Heart 1999;82:30-3.
2. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015;373:834-44.
3. Bradley EA, Ammash N, Martinez SC, et al. "Treat-to-close": Non-repairable ASD-PAH in the adult: Results from the North American ASD-PAH (NAAP) Multicenter Registry. Int J Cardiol 2019;291:127-133
4. Kijima Y, Akagi T, Takaya Y, et al. Treat and Repair Strategy in Patients With Atrial Septal Defect and Significant Pulmonary Arterial Hypertension. Circ J 2016;80:227-34.
5. Yan C, Pan X, Wan L, et al. Combination of F-ASO and Targeted Medical Therapy in Patients With Secundum ASD and Severe PAH. JACC Cardiovasc Interv 2020;13:2024-2034.
6. Takaya Y, Akagi T, Sakamoto I, Kanazawa H, Nakazawa G, Murakami T et al. Efficacy of Treat-and-Repair Strategy For Atrial Septal Defect With Pulmonary Arterial Hypertension. Heart 2021:[Epub Ahead of Print].
7. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:1494-1563.
8. Baumgartner H, De Backer J. The ESC Clinical Practice Guidelines for the Management of Adult Congenital Heart Disease 2020. Eur Heart J 2020;41:4153-4154.
9. Qureshi AM, Kenny D. Atrial Septal Defect Closure in Patients With Pulmonary Hypertension: Room for Punching a Hole in the Debate. JACC Cardiovasc Interv2020;13:2035-2037.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Congenital Heart Disease, CHD and Pediatrics and Imaging, CHD and Pediatrics and Prevention, Statins, Pulmonary Hypertension, Echocardiography/Ultrasound, Hypertension

Keywords: Hypertension, Pulmonary, Septal Occluder Device, Tadalafil, Pulmonary Arterial Hypertension, Pulmonary Artery, Arterial Pressure, Exercise Tolerance, Blood Pressure, Patient Selection, Dilatation, Ventricular Remodeling, Heart Defects, Congenital, Heart Septal Defects, Atrial, Vascular Resistance, Cardiac Catheterization, Vasodilator Agents, Echocardiography, Adrenergic Agents, Referral and Consultation, Hypertrophy, Morbidity

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