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Against all odds—late repair of multiple shunt lesions in a patient with Down syndrome: a case report

Abstract Background Children with congenital heart defects (CHD) usually undergo elective surgical repair of haemodynamically relevant shunt lesions within the first year of life. Due to susceptibility for pulmonary arterial hypertension (PAH) in patients with Down syndrome, repair is usually aimed for no later than 6 months of life. However, with rising immigration from developing countries to Europe, more patients with unrepaired CHD are diagnosed at a later age. Anatomical repair may be precluded, when advanced pulmonary vascular disease has been established. Case summary We report a 39-month-old male patient with Down syndrome with a large non-restrictive perimembranous ventricular septal defect, a large patent ductus arteriosus, and a secundum-type atrial septal defect with a prominent left-to-right shunting. Haemodynamic assessment revealed only a mild increase of pulmonary artery pressures (mPAP) with low pulmonary vascular resistance index (PVRi). Vasodilator testing led to a further increase of the left-to-right shunt and decrease of PVRi, suggesting operability. After careful consideration, the patient underwent complete surgical repair with a good post-operative clinical outcome. Cardiac catheterization 6 months after corrective repair showed a normal mPAP. No signs of PAH have been detected in the medium-term follow-up. Discussion Expertise, increased physician awareness, and a thorough pre-operative multidisciplinary evaluation are paramount to determine the best treatment approach for patients, who may present late with multiple shunts, and—in our case—underlying Down syndrome. Long-term close post-surgical follow-up in an expert centre is warranted to promptly diagnose and treat a possible late presentation of PAH appropriately.


Introduction
Depending on clinical presentation, children with congenital heart defects (CHD) and haemodynamically relevant shunt lesions usually undergo elective surgical repair within the first year of life, to avoid the development of progressive pulmonary vascular disease (PVD). 1,2 An even earlier timing for repair and shunt closure is recommended in those patients with associated Down syndrome, as irreversible PVD is thought to develop earlier in life and is often multifactorial. 3 However, late referral and diagnosis is still a problem, mainly in underserved countries, which may preclude anatomical repair, when advanced PVD has usually been established. 4 Pulmonary arterial hypertension (PAH)-CHD patients are at high risk for serious post-operative complications, including right heart failure and death. 5 Despite successful technical repair of their shunt lesion, survival prospects in those patients who develop severe progressive post-operative PAH is often worse compared to their natural course and the long-term development of an Eisenmenger physiology. 5 Even survivors with no immediate obvious PVD remain at risk for PAH, which is sometimes diagnosed years after repair. 2,6 Thus, it is critically important to decide whether a patient, who presents beyond infancy with a haemodynamically significant left-toright shunt, should undergo complete defect repair, with acceptable (peri-)operative risk and a favourable long-term outcome, with a low chance of developing late PVD. Herein, we highlight an unusual case of late presentation of a patient with intra-and extracardiac shunts and PAH, who successfully underwent corrective repair.

Case presentation
A 39-month-old refugee boy with Down syndrome presented with a large perimembranous ventricular septal defect (VSD), a secundumtype atrial septal defect (ASD II), and a patent ductus arteriosus (PDA). The diagnosis was made a month before his first consultation in our hospital. He presented with dyspnoea on exertion, being asymptomatic at rest (functional class: Panama II*, WHO II). 7 Adenoid and tonsillar hypertrophy have been noted. No previous surgery was reported. Cardiac auscultation revealed a mild systolic murmur at the left upper sternal border and a variable splitting of the second heart sound (S2) with an accentuated pulmonary component.

Learning points
• Late referral and diagnosis of paediatric patients with congenital heart defects is increasing with rising immigration from underserved countries.
• Careful clinical, echocardiographic, and haemodynamic assessment is warranted to assess patients' operability as irreversible pulmonary vascular disease may already have been established.
• In case of a surgical approach, close long-term follow-up in expert centres is advised, as the risk for post-operative pulmonary arterial hypertension persists even for decades after surgery.
. His baseline transcutaneous oxygen saturation at rest was 96%. His weight at presentation was 10.6 kg (<25th Down's centile) with a height of 83 cm (<25th Down's centile). Electrocardiogram (ECG) showed sinus rhythm with a slight rightward axis deviation and signs of right ventricular (RV) hypertrophy ( Figure 1A). Chest X-ray revealed biventricular dilatation and enlargement of the main pulmonary artery ( Figure 2). His transthoracic echocardiogram demonstrated a large non-restrictive perimembranous VSD, 12 mm in diameter, in addition to a smaller muscular VSD, both of which revealed left-to-right shunting ( Figure 3C and D and Video 1). Furthermore, a large PDA with a predominant left-to-right shunting in colour Doppler (Video 2) and an ASD II ( Figure 3A and B and Video 3) were depicted. Biventricular dilatation [left ventricular (LV) enddiastolic diameter 35 mm, z-score þ2.95; RV end-diastolic diameter 17 mm, z-score þ3.5] was present. Biventricular function (LV fractional shortening 52%, tricuspid annular plane systolic excursion 22 mm, z-score þ3.3) was well preserved.
The patient was discussed in the multidisciplinary team meeting. Given the favourable haemodynamic results, complete surgical repair, without leaving an atrial fenestration, was opted for. Eventually, the VSD was closed with an autologous pericardial patch and a direct suture of the ASD and PDA was performed at 3.5 years of age. Patient's post-operative course was uncomplicated. There were no echocardiographic evidence of any residual left-to-right shunt or signs  Figure 4A and B). In the absence of a sufficient tricuspid insufficiency to accurately estimate mPAP and the potential high risk for the development of post-operative PAH, in view of his late presentation and associated Down syndrome, it was decided to re-evaluate the patient invasively, in order not to miss a post-operative increase in the pulmonary vascular resistance (PVR). Invasive reassessment 6 months after surgical repair revealed a normal mPAP with a relative increase in PVRi ( Table 1). One explanation might be an increase of pulmonary flow (Qp) due to the abolished left-to-right shunting. However, it deserves further attention and close follow-up. In addition, a rightward shift of his QRS axis in the ECG has been noted ( Figure 1B), that could be explained by the haemodynamic change attributed to the shunt closure, abolishment of the pulmonary overcirculation and relief of strain from the overloaded LV. However, if right axis deviation persists or shifts even more to the right, it could be a sign of increasing RV pressure and strain with an increasing PVRi.
The patient remains asymptomatic on further follow-up with no clinical signs for pulmonary hypertension. In addition, he now shows catch-up growth, as his latest weight assessment was between 75th and 95th centile (before surgery <25th centile) for patients with Down syndrome and his height was between the 25th and 50th centile (before surgery <25th centile).

Discussion
The present case demonstrates that even among older children, with a susceptibility to develop PVD, multiple defect closure may still be feasible, with a good post-operative outcome. With rising immigration from developing countries to Europe, more children with unrepaired CHD are seen in outpatient clinics and are diagnosed and evaluated at a later age. 8 Careful clinical, echocardiographic, and haemodynamic assessment is warranted to determine, if a shunt lesion is still amenable to repair. Although long-term data are lacking, recommendations exist about the probability of repair. 9 Ruling out irreversible PVD plays a key role in the therapeutic decision-making process.
According to the latest update, PAH is haemodynamically defined as an increase in mPAP >20 mmHg and PVRi >3 WU*m 2 , with a low pulmonary capillary wedge pressure (PCWP<15 mmHg). 9 With a PVRi <6 WU*m 2 along with a PVRi/SVRi <0.3 a patient is deemed operable. Acute vasodilator testing is performed in patients with PAH-CHD to assess the significance and potential increase of a leftto-right shunt, PAH reversibility and thus, patients' operability. A > _20% fall in both PVRi and PVRi/SVRi ratio is considered a positive response and a patient is thought to be operable with final PVRi below 6 WU*m 2 and PVRi/SVRi <0.3. 10 The aetiology of PH in Down syndrome is often multifactorial. Although our patient had predisposing factors to develop irreversible PVD (post-tricuspid shunts, advanced age, and Down syndrome), 11 mPAP was only mildly elevated with an increased Qp and a considerably low PVRI. The baseline, Qp/Qs of 2.9 might have been overestimated under general anaesthesia. As our patient had adenoid and tonsillar hypertrophy, which is often associated with hypercapnia and additionally contributes to a higher PVRi, this finding may have prevented an even higher pulmonary blood flow and overcirculation. This reduction of shear stress may have prevented the onset of irreversible PVD. Sometimes an anatomically relevant VSD is partially functionally closed and flow diminishes via accessory tricuspid valve tissue, so the actual net flow via the VSD may have not been excessive. Moreover, unlike patients with a VSD and fixed PVR, in whom S2 often appears singular without any audible splitting, the variable splitting of S2 in our patient may be suggestive of reversible PAH. 11 Another hypothesis, why our patient has not developed PVD during the first years of life, is that he may have experienced a much slower postnatal adaptation and fall of his PVR. This would explain why our patient presented later in life, without expected symptoms of pulmonary overcirculation, like tachypnoea or failure to thrive. With a longer-standing increased Qp, as measured during cardiac catheterization, we would have expected him to be clinically more symptomatic. All these factors may have contributed to his relatively late clinical presentation, good tolerance, and benign haemodynamic findings.
PAH after surgical repair of shunt lesions has been reported in 7.4% of adult patients with CHD. 6 Another recent study demonstrated a PAH prevalence of 3% among patients with corrected simple defects, with age at repair and age at follow-up being closely associated with the risk of PAH even decades after surgery. 12 Consequently, there is a need for a long-term regular follow-up of these patients in expert centres, in order to early diagnose and promptly treat any possible late PAH presentation. If there were any concerns of rising PAPs and development of PH, we would consider repeat cardiac catheterization and proactive treatment with advanced pulmonary vasodilatory agents.

Conclusion
A thorough work-up and assessment of patients with haemodynamically relevant shunt lesions-presenting even beyond infancy-is mandatory, like in our patient, in whom successful repair and