Treat-and-repair Strategy for Atrial Septal Defect with Eisenmenger Syndrome due to Pulmonary Arterial Hypertension

Abstract

A 53-year-old man with Eisenmenger syndrome (ES), caused by a large secundum atrial septal defect (ASD) and severe pulmonary arterial hypertension (PAH), showed a marked hemodynamic improvement following an escalation of PAH-specific therapy. Surgical ASD closure using a fenestrated patch was successfully performed after a significant reduction in both the patient's pulmonary pressure and vascular resistance. This case highlights the potential utility of the “treat-and-repair” strategy in patients with ES and severe PAH, who exhibit a favorable response to medical therapy, resulting in both a symptomatic and hemodynamic improvement.

Introduction

In congenital heart defects that cause systemic-to-pulmonary shunts [e.g., ventricular septal defect (VSD), atrial septal defect (ASD), and patent ductus arteriosus], a persistent high pulmonary blood flow results in progressive pulmonary vascular remodeling, thus leading to elevated pulmonary vascular resistance (PVR) and pulmonary arterial hypertension (PAH). As PAH progresses, either shunt reversal (right to left) or a bidirectional flow occurs, leading to hypoxia with cyanosis and the development of Eisenmenger syndrome (ES) (1).

In shunt-associated PAH, defect closure is considered in mild PAH cases. However, in moderate to severe cases, an immediate closure may precipitate right-sided heart failure and death. Surgical or percutaneous closure is generally contraindicated in ES (1). Heart-lung transplantation, or combined lung and cardiac surgery, remains the only curative option; however, its implementation is limited in Japan owing to surgical complexity and donor limitations (2).

Recent advancements in pharmacological therapies have made it possible to evaluate pulmonary vascular reversibility. If PVR decreases and pulmonary hemodynamics improves following PAH-targeted therapy, then the surgical or transcatheter repair of the defect, referred to as the “treat-and-repair” strategy, has shown promising results (3).

However, cases of ASD with ES that are successfully treated using this approach are rare. In this report, we present a case of ASD with severe PAH and ES, in which the treat-and-repair strategy led to an improvement in symptoms and hemodynamics.

Case Report

The patient was a 53-year-old man who had experienced exertional dyspnea [New York Heart Association (NYHA) Class II] for three years. Two years prior to presentation, his peripheral oxygen saturation (SpO₂) dropped to 85% after walking 200 m. His symptoms worsened over time, and 1 month prior to referral, he experienced a further drop in SpO₂ to 77% with stair climbing and progression to NYHA class III. The patient had no history of hypertension, diabetes, other cardiovascular risk factors, or regular medication use but he had smoked 30 cigarettes daily for 25 years. On initial examination, his blood pressure was 126/80 mmHg, pulse was 127 bpm (regular), and SpO₂ was 90% (room air), with jugular venous distention, no lung rales, Levine grade 2/6 systolic murmur in the 3rd left intercostal space, fixed splitting of the second heart sound, bilateral lower extremity edema, digital clubbing, and cyanotic skin discoloration.

Laboratory data showed a hemoglobin level of 15.9 g/dL, hematocrit of 50%, and a mean corpuscular volume of 103 fL, indicating mild erythrocytosis with macrocytosis. His liver enzyme levels were within the normal limits: aspartate aminotransferase, 26 IU/L; alanine aminotransferase, 22 IU/L; lactate dehydrogenase, 231 IU/L; and alkaline phosphatase, 74 IU/L. Renal function tests revealed a serum creatinine level of 1.3 mg/dL and an estimated glomerular filtration rate of 46 mL/min/1.73 m², consistent with moderate chronic kidney disease. Pulmonary function testing demonstrated a percent forced expiratory volume in 1 s of 65%, percent vital capacity of 127%, and percent diffusing capacity for carbon monoxide of 53%, indicating obstructive ventilatory impairment with a reduced gas exchange capacity.

Electrocardiography revealed sinus tachycardia (heart rate, 120 bpm), right-axis deviation, prominent R waves in leads V1-V3, deep S waves in leads V2-V6, and ST-segment depression in leads II, III, aVF, and V1-V5 (Fig. 1A). Chest radiography showed prominence of the left second aortic knob, right cardiac border, and left fourth arch, suggesting right atrial and ventricular enlargement (Fig. 2A). Transthoracic echocardiography revealed no left ventricular wall motion abnormalities (left ventricular ejection fraction, 64%) but showed marked right ventricular enlargement compressing the left ventricle with a D-shaped morphology during systole (Fig. 3A, B). Tricuspid regurgitation grade 3/4 was present, with a pressure gradient of 86 mmHg, thus indicating severe PAH. A large secundum-type ASD with bidirectional shunting was observed along with a small degree of pericardial effusion. Transesophageal echocardiography revealed a large defect measuring 40 mm×30 mm, which was unsuitable for device closure (Fig. 3C).

Figure 1.

Twelve-lead electrocardiogram. (A) At initial presentation: sinus tachycardia, right-axis deviation, prominent R waves in V1-V3, deep S waves in V2-V6, and ST depression in II, III, aVF, and V1-V5. (B) After medical therapy and atrial septal defect closure: an improvement in heart rate and right ventricle loading was observed.

Figure 2.

Chest radiography. (A) At initial presentation: prominent pulmonary artery, right heart border, and left fourth arch suggestive of right heart enlargement. (B) After treatment and atrial septal defect closure: a reduction in cardiomegaly and pulmonary artery prominence was observed.

Figure 3.

Transthoracic and transesophageal echocardiography. (A) Subxiphoid view: large secundum-type atrial septal defect (ASD) with right atrial and right ventricular enlargement. (B) Parasternal short-axis view: D-shaped left ventricle during systole due to right ventricular compression; pericardial effusion is visible. (C) Transesophageal echocardiography: large atrial septal defect measuring 40×30 mm. (D) Post-ASD closure: slight shunting from the left to the right atrium through the fenestration. (E) Resolution of pericardial effusion and an improved left ventricular shape with a reduced right ventricular size postoperatively.

Right heart catheterization revealed a mean pulmonary arterial pressure (mPAP) of 58 mmHg, cardiac index of 2.6 L/min/m², mean left atrial pressure of 10 mmHg, mean right atrial pressure of 11 mmHg, and PVR of 9.8 Wood units (WU). The pulmonary-to-systemic blood flow ratio (Qp/Qs) was 1.0, based on the oxygen saturation measured at multiple sites: the inferior vena cava (68%), superior vena cava (63%), right atrium (70%), right ventricle (70%), and pulmonary artery (70%). The systemic arterial oxygen saturation was 88%. Left heart oxygen saturation, measured using the transseptal approach, was 95% in the left atrium and 90% in the left ventricle. A right-to-left shunt was inferred from a drop in oxygen saturation from the left atrium to the left ventricle (95-90%), leading to a diagnosis of ASD complicated by ES due to severe PAH. This condition had not been previously diagnosed or identified for the first time during evaluation.

Following the European Society of Cardiology (ESC) guidelines for adult congenital heart disease, we initiated PAH-specific therapy targeting a PVR ＜5.0 WU and Qp/Qs ＞1.5 (1). Riociguat, selexipag, and macitentan were sequentially introduced and titrated to maximal doses (7.5, 3.2, and 10 mg) (Fig. 4). Home oxygen therapy was initiated at a rate of 1 L/min via nasal cannula because of hypoxemia. Serial cardiac catheterizations were performed to accurately assess the hemodynamics, and the following values were obtained: after 6 months, hemodynamic improvement was observed: mPAP, 44 mmHg; PVR, 4.1 WU; and Qp/Qs, 1.9. With oxygen loading (10 L/min for 10 min), the mPAP decreased to 42 mmHg, PVR to 4.1 WU, and the Qp/Qs increased to 2.3. Under nitric oxide inhalation (10 ppm for 5 min), the mPAP was 45 mmHg, PVR was 5.0 WU, and Qp/Qs was 1.6. Ten months after initiating treatment, dyspnea worsened again, and the hemodynamics deteriorated (mPAP, 38 mmHg; PVR, 5.7 WU; Qp/Qs, 1.2) with increased right-to-left shunting. Epoprostenol infusion was added and titrated to 12 ng/kg/min, which improved hemodynamics to an mPAP of 34 mmHg, PVR of 3.7 WU, Qp/Qs 1.7. The right ventricular function was carefully evaluated using transthoracic echocardiography (TTE) after drug therapy. The right ventricular end-diastolic area index was 24 cm²/m², fractional area change was 25%, tricuspid annular plane systolic excursion was 24 mm, and tissue Doppler-derived tricuspid annular systolic velocity (S′) was 16 cm/s. These findings indicate a preserved longitudinal right ventricular systolic function, which supports the feasibility of ASD closure in this patient. Fifteen months after initiating therapy, surgical closure of the ASD was performed using a 6-mm fenestrated pericardial patch. The heart was approached via standard median sternotomy, followed by right atriotomy. Left atrial appendage resection and isthmus block were performed to reduce the risk of atrial arrhythmias.

Figure 4.

Clinical course before and after atrial septal defect (ASD) closure.

Three weeks postoperatively, the mPAP decreased to 23 mmHg, the PVR to 1.9 WU, and the Qp/Qs to 1.7. Oral selexipag was discontinued owing to the patient's hemodynamic improvement. At 5 months postoperatively, as mPAP increased to 33 mmHg and PVR to 3.7 WU, oral selexipag was resumed, and the dose of epoprostenol was increased to 18 ng/kg/min. At 12 months postoperatively, under treatment with epoprostenol (18 ng/kg/min), riociguat (7.5 mg), selexipag (1.6 mg), and macitentan (10 mg), the mPAP was 35 mmHg, the PVR was 2.8 WU, and the Qp/Qs was 1.2. Electrocardiography revealed an improvement in the right ventricular strain, with a resolution of tachycardia and a decrease in the depth of the S-waves in leads V4-V6 (Fig. 1B). Chest radiography revealed reduced cardiomegaly (Fig. 2B). Transthoracic echocardiography revealed slight shunting from the left atrium to the right atrium through fenestration, disappearance of pericardial effusion, a reduction in right ventricular enlargement, and an improvement of the D-shaped left ventricle (Fig. 3D, E). The patient's NYHA class improved to Class II.

Discussion

ASD accounts for approximately 7-13% of all congenital heart defects and represents 35-40% of congenital heart diseases in patients aged ＞40 years (2,4). Secundum defects are the most common among the various type of ASDs. Many patients remain asymptomatic until adulthood, leading to a delayed diagnosis. In Japan, an estimated 5,000 adult patients have uncorrected congenital heart disease and severe PAH (5).

The direction and volume of interatrial shunting are determined by defect size, atrial pressure gradient, ventricular compliance, and PVR. While ASDs typically result in left-to-right shunts, the progression of pulmonary hypertension can reverse the shunt, resulting in ES. Small ASDs rarely cause PAH, but large defects, as in this case, can result in significant right-sided volume overload and increased pulmonary arterial pressure, leading to adult-onset PAH (1).

PAH secondary to congenital heart disease is thought to be triggered by the endothelial shear stress caused by an excessive pulmonary blood flow. Therefore, surgical or catheter-based ASD closure is desirable to prevent pulmonary vascular damage. In adults, ASD closure is generally indicated when Qp/Qs is ＞1.5-2.0. For catheter-based closure, a significant left-to-right shunt with right atrial or right ventricular enlargement and a PVR ＜5 WU is considered a class I indication regardless of symptoms (1,2).

Historically, guidelines have contraindicated shunt closure in patients with high PVR. According to earlier ESC guidelines, shunt closure was considered feasible when the PVR was ＜2.3 WU, contraindicated when it was ＞4.6 WU, and individualized for values between 2.3 and 4.6 WU (6). Therefore, the closure was limited to patients with mild PAH. However, with the advent of PAH-specific therapies, some patients with moderate-to-severe PAH have demonstrated improved pulmonary hemodynamics and thus have become candidates for shunt closure after medical treatment (3).

In Japan, registry data have supported the use of the treat-and-repair strategy, where ASD closure is considered when the PVR is ＜5.0-7.0 WU and Qp/Qs is ＞1.5. Medical therapy led to improvements in Qp/Qs (from 1.9±0.8 to 2.4±1.2), PVR (from 6.9±3.2 to 4.0±1.5 WU), and mPAP (from 45±15 mmHg to 35±9 mmHg), with safe outcomes following transcatheter closure (7).

A US multicenter study of 69 patients who were initially deemed inoperable showed that 19 patients were suitable for closure after targeted PAH therapy, demonstrating improvements in pulmonary pressure and right heart function compared with those who did not undergo repair (8). In this study, a PVR of ＞4.6-7 WU was considered high-risk, and therefore, a “non-correctable” defect.

In a study by Akagi et al. involving 25 patients with ASD, VSD, and PAH associated with congenital heart disease (PAH-CHD) with a PVR of ≥5 WU, 20 patients successfully underwent shunt closure, while five patients were not eligible for closure and were thus considered to be Eisenmenger-like cases. Surgical intervention was performed in patients who achieved a PVR of ＜6 WU, Qp/Qs of ≥1.3, and resting SpO₂ of ≥90% after PAH-targeted therapy. In the surgical group, the mPAP decreased from 53±13 mmHg to 43±20 mmHg after medical therapy and further to 29±12 mmHg after surgery. The PVR decreased from 9.6±2.6 to 5.0±3.4 WU with medical therapy and to 4.8±2.2 WU after surgery. The Qp/Qs improved from 1.5±0.6 to 2.4±1.3 with medical therapy and then decreased to 1.0±0.1 after surgical closure, thus indicating a successful reduction of left-to-right shunting and pulmonary artery pressure. Five patients who did not meet the repair criteria did not undergo repair and showed limited hemodynamic improvement (9). These results suggest that in patients who are responsive to treatment, the pulmonary vasculature retains plasticity and may permit safe ASD repair even in cases of moderate-to-severe PAH (10,11).

The current ESC guidelines state that when PVR is between 3 and 5 WU and Qp/Qs ＞1.5, closure may be considered (Class IIa). If the PVR is ＞5 WU, closure should only be considered after medical therapy; if the hemodynamics improve with Qp/Qs ＞1.5, fenestrated closure may be considered (Class IIb) (1). However, there is limited evidence regarding the optimal duration of the treat-and-repair strategy before and after surgery and the hemodynamic criteria guiding this approach.

In our case, the initial hemodynamics were not favorable for closure (PVR, 9.8 WU; Qp/Qs, 1.0), but medical therapy, including oral agents and intravenous epoprostenol, improved the PVR to 3.7 WU and Qp/Qs 1.7. Surgical intervention was performed when the PVR decreased further to ＜5 and Qp/Qs exceeded 1.5, according to ESC guidelines. Surgical intervention could have been justified at six months following medical therapy with respect to early intervention. The postponement was primarily due to the patient's preference, including the reluctance to undergo surgical repair after transfer to the surgical center. For better outcomes in patients with congenital heart disease who may require surgical repair, early consultation with the surgical center and close communication are essential. Surgical intervention rather than device closure in this case was selected because of the large size of the ASD (38 mm) (1). In addition, complete closure of the ASD carries the risk of early postoperative complications such as PAH crisis and right heart failure. Previous studies have reported the efficacy of fenestrated ASD closure with a 3-8 mm fenestration in patients with PAH or ES, allowing for atrial decompression while minimizing hypoxia-related complications (12). To reduce the risk of early postoperative hemodynamic instability, a relatively large 6 mm fenestration was created in the patch closure of the ASD in this case. If pulmonary hypertension further improves and left-to-right shunting becomes hemodynamically significant, then transcatheter closure of the fenestration may be warranted using devices typically used for patent foramen ovale occlusion (13). In the present case, postoperative echocardiography revealed a spontaneous shrinkage of the fenestration by approximately 3 mm. As this was deemed hemodynamically insignificant, no additional intervention was performed.

This strategy resulted in a significant symptomatic and hemodynamic improvement. In the future, introducing inhaled treprostinil or subcutaneous sotatercept injection into oral vasodilators may lead to the discontinuation of intravenous epoprostenol treatment.

Aggressive PAH-targeted therapy following standard PAH protocols is recommended for ES and PAH-CHDs. Although specific evidence is limited, combination therapy with endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins is commonly used. In severe cases, the early initiation of intravenous prostacyclin is ideal (1).

In conclusion, patients with ES secondary to PAH may benefit from a treat-and-repair approach if the pulmonary vascular reversibility is maintained. More clinical evidence is required; however, this strategy offers a promising alternative in selected cases.

The authors state that they have no Conflict of Interest (COI).