Polysplenia Syndrome as a Risk Factor for Early Progression of Pulmonary Hypertension

Abstract

Background: Recent progress in surgical and intensive care has improved the prognosis of congenital heart disease (CHD) associated with heterotaxy syndrome. Less is known, however, about pulmonary vascular complications in these patients.

Methods and Results: We reviewed medical records of 236 patients who were diagnosed with polysplenia syndrome at 2 institutions for pediatric cardiology in Japan from 1978 to 2015. We selected and compared the clinical records of 16 patients with polysplenia who had incomplete atrioventricular septal defect (AVSD) as the polysplenia group, and 22 age-matched patients with incomplete AVSD without any syndromes including polysplenia as the control group. Although the severity of systemic to pulmonary shunt was not significantly different between the groups, mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance index (PVRI) were significantly higher in the polysplenia group than the control (mPAP, 37.3 vs. 19.1 mmHg, P=0.001; PVRI, 5.7 vs. 1.4 WU∙m², P=0.014) before surgical intervention. On regression analysis, polysplenia influenced the development of pulmonary hypertension (PH) regardless of age at evaluation or degree of systemic to pulmonary shunt in the patients with incomplete AVSD.

Conclusions: Polysplenia syndrome is an independent risk factor for CHD-associated PH. Earlier intervention may be required to adjust the pulmonary blood flow in polysplenia syndrome with CHD to avoid the progression of PH.

Heterotaxy or isomerism syndrome is a birth defect resulting from disturbance of left-right axis patterning during embryogenesis.¹ Generally, heterotaxy syndrome is classified into 2 major subtypes: bilateral right-sidedness, which is defined as right isomerism or asplenia syndrome;² and bilateral left-sidedness, which is defined as left isomerism or polysplenia syndrome,³ although the status of the spleen does not always correlate with the presumed right or left sidedness.^4–6

Given that the heart is the organ that forms left-right axis patterning in the earliest period during embryogenesis, heterotaxy syndrome is frequently associated with congenital heart disease (CHD).⁷ Patients with asplenia characteristically have total anomalous pulmonary venous connection, unbalanced atrioventricular septal defect (AVSD), double outlet right ventricle, pulmonary atresia or stenosis, absent coronary sinus and bilateral right atrial-like appendages,^6,8 whereas patients with polysplenia typically have interruption of the inferior vena cava (IVC) with azygos or hemiazygos continuation, AVSD with more often balanced ventricles, and bilateral left atrial-like appendages.^6,9 The prognosis of heterotaxy syndrome is generally subject to the severity of CHD,¹⁰ moreover, there are many complications in multiple other organ systems in heterotaxy syndrome, and these complications influence the risk of cardiac surgery.¹¹

Of the extracardiac complications in patients with CHD, pulmonary hypertension (PH) is an important factor in the indication for surgical intervention and is essential for prognosis.^12–14 Large systemic to pulmonary, or left to right, shunt results in CHD-related PH, hence heterotaxy syndrome may develop into PH because of its high frequency of CHD. PH is more common in adult patients with isomerism, especially with anomalous pulmonary venous connection, which is typically associated with asplenia.¹⁵ An association has also been reported between PH and asplenia. PH may be caused by thromboembolism due to lack of adequate filtration of thrombocytes and erythrocytes in patients with asplenia due to the absence of the spleen.^16–18 With regard to polysplenia, PH has been suggested to be associated with extracardiac abnormality,^19–22 but other factors including CHD seem to be involved, although they have not been identified as yet.

In this study, we showed that polysplenia syndrome is an independent risk factor for CHD-associated PH during early infancy. Also, in this first multicenter study we found that patients with incomplete AVSD and polysplenia rapidly develop PH compared with those without polysplenia.

Methods

Subjects

The subjects consisted of 236 consecutive patients who were diagnosed with polysplenia syndrome at Keio University Hospital, Tokyo, Japan, and Tokyo Women’s Medical University Hospital, Tokyo, Japan between 1978 and 2015. All patients underwent an assessment of structural heart disease and PH on echocardiography, electrocardiogram and chest X-ray.

The inclusion criteria were age <30 years at diagnosis; follow-up >6 months; and cardiac catheterization data under local or general anesthesia. Using these criteria, 16 polysplenia patients with incomplete AVSD were selected from the 236 polysplenia patients, and 22 non-polysplenia patients with incomplete AVSD were selected from 29,023 patients with CHD (5,323 patients from the hospital of Keio University School of Medicine and 23,700 patients from the hospital of Tokyo Women’s Medical University).

The exclusion criteria were presence of other chromosome abnormality (e.g., Down syndrome), or other systemic syndromes/associations [e.g., CHARGE syndrome (OMIM #214800), VACTERL association (OMIM %192350), asplenia] except for polysplenia. We also excluded patients with any extra-cardiac disease or complications that may affect the development of PH, such as respiratory and gastrointestinal diseases. For the phenotype of cardiac defect, we excluded any CHD with interventricular shunt and defects in pulmonary circulation (e.g., pulmonary stenosis, partial anomalous pulmonary venous connection).

Finally, 38 patients with incomplete AVSD were recruited: 16 patients with polysplenia (the polysplenia group), and 22 patients without polysplenia (the control group). Medical charts, cardiac catheterization data and other associated clinical findings were reviewed retrospectively to obtain the detailed state, treatment and outcomes of PH. Follow-up data were obtained from medical charts and correspondence with the referring physicians. The institutional review board approved the study protocol.

Diagnostic Criteria

Polysplenia syndrome is diagnosed on ultrasonography, with (1) interruption of the IVC with azygous continuation and/or (2) ambiguous viscero-atrial situs including bilateral symmetrical liver, right-sided stomach or abnormal number and position of spleen.

Incomplete AVSD was diagnosed on echocardiography on the basis of common AV valve and/or primum atrial septal defect, without ventricular septal defect.

The diagnosis of PH was based on the presence of elevated mean pulmonary artery pressure (mPAP; ≥25 mmHg) and pulmonary vascular resistance (PVR; >3 Wood units) measured on catheterization.^23,24

Statistical Analysis

Dichotomous or categorical variables were compared between the polysplenia and control groups using Fisher’s exact test, as appropriate. Continuous variables were compared between groups using Mann-Whitney U-test or linear regression analysis with forced entry method. P<0.05 was used to reflect statistical significance for all inferential statistics. Analysis was done using IBM SPSS statistics 23 (IBM, Armonk, NY, USA).

Results

Early Development of PH in Incomplete AVSD With Polysplenia

The subjects consisted of 16 polysplenia patients with incomplete AVSD, and 22 controls who had incomplete AVSD without any syndromes, including polysplenia, and who met all the other eligibility criteria (Tables 1,2). Patients 1,10,11 (Table 1) were judged as inoperable due to suprasystemic pulmonary artery pressure, which is a risk factor for pulmonary hypertensive crisis after surgery. All 3 patients had no acute pulmonary vascular reactivity to oxygen or tolazoline hydrochloride in cardiac catheterization. Of note, unlike these 3 patients, patient 2 with high PVR index (PVRI; 16 Wood units∙m²) could undergo corrective surgery because of good acute pulmonary vascular reactivity to oxygen, resulting in residual PH after surgery. mPAP and PVR measured on cardiac catheterization before AVSD repair were significantly higher in the polysplenia group than in the control group (mPAP, 37.3 vs. 19.1 mmHg, P=0.001; PVRI, 5.7 vs. 1.4 Wood units∙m², P=0.014; Figure 1). Interestingly, on linear regression analysis polysplenia was an independent risk factor for increasing mPAP and PVR in patients with incomplete AVSD regardless of pulmonary-systemic blood flow ratio (Qp/Qs) or age at diagnosis, both of which are the most important predictors for developing irreversible PH (Table 3).²⁵ Using the PH criteria (mPAP ≥25 mmHg and PVR >3 Wood units), the proportion of patients with PH in the polysplenia group was significantly higher than in the control group before surgery for AVSD repair (56 vs. 9%, P=0.001). In contrast, later age at evaluation (>7 months) and high Qp/Qs (>2.0) were not significantly associated with the development of PH in patients with incomplete AVSD (Table 4).

Table 1. Polysplenia Patient Characteristics and Hemodynamics

Patient ID no.	Total follow-up (months)	Age at CC (months)	Preoperative mPAP (mmHg)	Preoperative AVVR	Other hemodynamic abnormalities	Diagnostic basis for PH	Age at surgery (months)	Postoperative follow-up (months)†	Residual PH after surgery	Postoperative RVP/LVP ratio	Diagnostic basis for postoperative PH	Outcome
1	6	2	66	Mild or less	None	CC	NI	NA	NA	NA	TTE	Dead
2	428	15	46	Mild or less	None	CC	17	16	Yes	0.6	CC	Alive
3	28	3	24	Moderate	None	CC	4	10	Yes¶	0.6	CC	Dead
4	126	18	28	Moderate	None	CC	72	<1	No	<0.4	TTE	Alive
5	476	359	48	ND	None	CC	362	24	Yes	>0.6	CC	Alive
6	263	11	35	ND	None	CC	14	<1	Yes	0.5	TTE	Alive
7	156	2	50	ND	None	CC	63	<1	Yes	1	TTE	Alive
8	9	4	31	Mild or less	None	CC	96	1	Yes	>0.6	TTE	Alive
9	72	36	45	Mild or less	None	CC	60	12	Yes	1	CC	Dead
10	30	25	61	Mild or less	PDA‡	CC	NI	NA	NA	NA	TTE	Dead
11	24	61	62	Mild or less	None	CC	NI	NA	NA	NA	TTE	Alive
12	12	11	19	Mild or less	None	CC	124	<1	No	<0.4	TTE	Alive
13	24	12	22	Mild or less	None	CC	24	<1	No	<0.4	TTE	Alive
14	60	60	20	Mild or less	None	CC	60	<1	No	<0.4	TTE	Alive
15	36	12	18	Moderate	CoA§, PDA‡	CC	12	<1	No	<0.4	TTE	Alive
16	126	71	22	ND	None	CC	72	117	No	0.4	CC	Alive

^†Time from operation to postoperative PH evaluation/diagnosis, or follow-up interval after the decision of inoperability; ^¶postoperative onset of PH; ^§only mild CoA without indication for surgical repair; ^‡small PDA without significant shunt. AVVR, atrioventricular valvular regurgitation; CC, cardiac catheterization; CoA, coarctation of aorta; LVP, left ventricular pressure; mPAP, mean pulmonary artery pressure; NA, not applicable; ND, not determined; NI, no indication for surgical repair; PDA, patent ductus arteriosus; PH, pulmonary hypertension; RVP, right ventricular pressure; TTE, transthoracic echocardiography.

Table 2. Control Group Characteristics and Hemodynamics

Patient ID no.	Total follow-up (months)	Age at CC (months)	Preoperative mPAP (mmHg)	Preoperative AVVR	Other hemodynamic abnormalities	Age at surgery (months)	Postoperative follow-up (months)†	Residual PH after surgery	Postoperative RVP/LVP ratio	Diagnostic basis for postoperative PH	Outcome
1	22	24	23	Moderate	None	25	<1	No	<0.4	TTE	Alive
2	8	76	15	Mild or less	None	94	<1	No	<0.4	TTE	Alive
3	115	63	14	Moderate	None	68	<1	No	<0.4	TTE	Alive
4	143	79	16	Moderate	None	152	<1	No	<0.4	TTE	Alive
5	6	31	15	Moderate	None	33	<1	No	<0.4	TTE	Alive
6	186	1	21	Moderate	None	2	8 m	No	0.3	CC	Alive
7	3	51	15	Mild	None	52	<1	No	<0.4	TTE	Alive
8	229	20	15	Mild	None	170	<1	No	<0.4	TTE	Alive
9	224	33	25	Moderate	None	34	33 m	No	0.3	CC	Alive
10	235	39	20	Mild	None	32	<1	No	<0.4	TTE	Alive
11	86	27	22	Moderate	None	31	<1	No	<0.4	TTE	Alive
12	275	9	22	Mild	None	24	<1	No	<0.4	TTE	Alive
13	290	4	13	Moderate	None	17	<1	No	<0.4	TTE	Alive
14	21	45	16	ND	None	66	<1	No	<0.4	TTE	Alive
15	143	7	20	ND	None	15	<1	No	<0.4	TTE	Alive
16	168	28	18	ND	None	42	<1	No	<0.4	TTE	Alive
17	214	31	15	ND	None	58	<1	No	<0.4	TTE	Alive
18	19	16	13	ND	None	35	<1	No	<0.4	TTE	Alive
19	3	25	17	Mild	None	27	<1	No	<0.4	TTE	Alive
20	155	24	55	ND	None	24	<1	No	<0.4	TTE	Alive
21	134	63	18	ND	None	63	<1	No	<0.4	TTE	Alive
22	2	1	13	ND	None	3	<1	No	<0.4	TTE	Alive

^†Time from operation to postoperative CC, or follow-up interval after operation. Abbreviations as in Table 1.

Figure 1.

(A) Mean pulmonary artery pressure (mPAP) and (B) pulmonary vascular resistance index (PVRI) according to presence of polysplenia in patients with incomplete atrioventricular septal defect. Data given as mean and standard error.

Table 3. Predictors of Increased mPAP and PVR in Polysplenia Patients With Incomplete AVSD

	Unstandardized coefficients		Standardized coefficients
	B	SE	β	P-value
mPAP
Polysplenia	17.027	4.789	0.551	0.001
Age at evaluation	0.23	0.035	0.092	0.660
Qp/Qs	−0.594	1.616	−0.057	0.716
PVR
Polysplenia	3.458	1.468	0.385	0.024
Age at evaluation	−0.010	0.011	−0.131	0.379
Qp/Qs	−0.714	0.496	−0.235	0.159

PVR, pulmonary vascular resistance; Qp/Qs, ratio of pulmonary to systemic blood flow. Other abbreviations as in Table 1.

Table 4. Risk Factors for CHD-Associated PH in Polysplenia Patients With Incomplete AVSD^†

	PH (+) (n=10)	PH (−) (n=28)	P-value
Polysplenia (n=16)	9 (56)	7 (44)	0.001
Age at evaluation >7 months (n=31)	8 (26)	23 (74)	1.000
Qp/Qs >1.5 (n=30)	6 (21)	23 (79)	0.170
Qp/Qs >2.0 (n=21)	6 (29)	15 (71)	1.000

Data given as n (%). ^†Fisher’s exact test. CHD, congenital heart disease. Other abbreviations as in Tables 1,3.

Prevalence of Severe and Irreversible PH

Eight patients with polysplenia and PH had undergone surgical repair, 7 of whom (87.5%) had residual PH after surgery, whereas in the control group the 2 patients who developed PH before surgical repair had improvement of PH after surgery. In the polysplenia group, all 9 patients with preoperative PH had poor outcome in terms of residual PH after surgery or inoperability due to severe PH, whereas all 22 patients in the control group had a good prognosis, with no residual PH (residual PH, 62.5% vs 0%, P<0.001).

With regard to Qp/Qs ratio, in patients with Qp/Qs >1, the polysplenia group had higher mPAP and lower Qp/Qs than the control group (Figure 2). This suggests that PH may develop earlier even with lower increased pulmonary blood flow in incomplete AVSD patients with polysplenia than in those without polysplenia. Furthermore, 3 polysplenia patients showed Qp/Qs ≤1, 2 of whom had PH, whereas no subject showed Qp/Qs ≤1 in the control group. PVRI was 15 and 25 Wood units∙m² in these 2 patients. This further suggests that pulmonary vascular obstructive disease may develop very early in some patients with incomplete AVSD and polysplenia.

Figure 2.

Mean pulmonary artery pressure (mPAP) vs. ratio of pulmonary to systemic blood flow (Qp/Qs) in the (A) polysplenia group (polysplenia+incomplete atrioventricular septal defect [AVSD]; n=16); and (B) control group (incomplete AVSD; n=22).

Discussion

Here we have shown that polysplenia is a risk factor for CHD-associated PH. There have been few studies on PH with polysplenia syndrome, although we have previously reported a close association between CHD-associated PH and polysplenia in a Japanese single-center study.²⁶ Generally, the hemodynamic status of incomplete AVSD is similar to that of large secundum atrial septal defects with large left-right pre-tricuspid intracardiac shunt, and the association of PH, especially during early infancy, is rare as seen in the present control group without polysplenia.²⁷ This is in contrast to the fact that complete AVSD usually generates PH due to excessive pulmonary flow during early infancy. Given that age at cardiac catheterization and mean Qp/Qs were not significantly different between the polysplenia and control groups, this suggests that the pulmonary vasculature in patients with polysplenia has a tendency toward the early development of PH, caused by increased pulmonary blood flow due to left to right intracardiac shunt, including pre-tricuspid shunt.

In terms of other risk factors, the influence of AV valve regurgitation (AVVR) should be considered. Adatia and Beghetti reported that elevated pulmonary venous pressure and left atrial pressure is a risk factor for PH crisis in the perioperative period in CHD.²⁸ Therefore, severe AVVR could additionally influence the rapid progression of PH in the clinical course of AVSD. In this study, however, some patients with polysplenia developed severe PH in early infancy and had residual PH after corrective surgery, even though preoperative AVVR was not severe. Taken together, the cause and severity of PH may be difficult to explain by the magnitude of AVVR alone in these patients. This suggests that polysplenia is an essential risk factor for rapid progressive PH independent of the severity of AVVR, although its influence needs to be considered.

A total of 5–17% of patients with polysplenia have congenital portosystemic venous connection.^19,20 The congenital portosystemic venous connection may cause portopulmonary hypertension. Kobayashi et al reported a patient with polysplenia syndrome and PH due to congenital extrahepatic portosystemic shunts.²¹ Law et al also reported 2 cases of polysplenia and PH due to congenital absence of the portal vein.²² These reports suggest the close association between congenital portosystemic venous connection and PH in polysplenia syndrome. In the present study, however, all polysplenia patients had assessment of congenital portosystemic venous connection on abdominal echography, computed tomography or magnetic resonance imaging, and it was confirmed that they had no portosystemic shunt. This suggests that PH may develop in polysplenia syndrome even without portosystemic shunt.

The detailed etiology of PH in polysplenia patients other than portosystemic shunt has not been clarified. One possibility is the reduction in ventilation volume and vascular bed resulting from bilateral bi-lobed lung morphology.²⁹ Bilateral bi-lobed lungs are present in 48.9–55% of autopsy cases of polysplenia.^9,30 Reduction of lung volume and pulmonary vascular bed in polysplenia syndrome may be vulnerable to increased pulmonary blood flow due to left to right intracardiac shunt, and susceptible to the elevation of PVR, eventually resulting in PH even by pre-tricuspid shunt, compared with normal lungs.

With regard to the microscopy of the lungs in polysplenia syndrome, Papagiannis et al reported a large, thin-walled, irregular vascular channel parallel to the pleura in a patient with polysplenia and portosystemic anastomosis.³¹ Although these findings were consistent with the development of arteriovenous anastomosis due to portosystemic shunt,³¹ they may not be the polysplenia-specific phenotype.³² There has been no report on the lung tissue pathology in polysplenia patients with PH without portosystemic anastomosis. Further detailed studies using biopsy or autopsy are required to identify the polysplenia-specific pathological features associated with early progression of PH.

Another possibility may be that ciliary dyskinesia associated with polysplenia could result in PH. The co-existence of polysplenia and abnormal respiratory cilia has been confirmed.^33–35 Nasal nitric oxide (NO) was also recently shown to be significantly decreased in patients with isomerism due to ciliary dyskinesia.³⁶ A signaling defect involving NO is thought to play an important role in the pathogenesis of PH, and reduction in the fractional NO concentration (FE_NO) in exhaled breath in idiopathic PH.³⁷ Furthermore, FE_NO has been correlated with hemodynamic severity of disease, prognosis and response to therapy.³⁸ Taken together, defective respiratory cilia in ciliary dyskinesia may result in the chronic impairment of NO production in the respiratory system, and eventually play a role in the development of PH, although the detailed mechanism is still obscure.

The medical treatment for PH in patients with polysplenia is still challenging. In the present study, half of the patients with PH had residual PH even after surgical repair in the polysplenia group, whereas in the control group no patients had residual PH. This suggests that the effect of drug therapy is uncertain, and that irreversible pulmonary vascular obstructive disease could progress rapidly in the patients with polysplenia and CHD with left to right shunt. Myers et al reviewed the operability of patients with PH associated with CHD and concluded that each patient should be assessed on an individual basis, based on type of defect, risk of surgical repair, or risk of developing persistent PH after repair.³⁹ We, thus, believe that intracardiac repair, even for pre-tricuspid shunt, should be performed earlier in patients with polysplenia than in those without polysplenia in order to avoid the development of irreversible PH.

Conclusions

Polysplenia syndrome carries a risk of development of PH from early infancy. It is therefore necessary to prepare for the rapid progression of PH from the early postnatal period in the case of polysplenia even with incomplete AVSD, which is not usually associated with PH. Intensive medical treatment and early surgical intervention for CHD-associated PH may be required, although this is still challenging, in patients with polysplenia and CHD.

Acknowledgments

We would like to thank all the clinicians involved with patient care at Keio University Hospital and Tokyo Women’s Medical University Hospital.

Disclosures

The authors declare no conflicts of interest.

Grants

This work is supported by Acterion Academia Prize 2015 (A.S.) and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Grant Numbers 25293238 and 16H05359) (H.Y.).

References

• 1.   Jacobs JP, Anderson RH, Weinberg PM, Walters HL 3rd, Tchervenkov CI, Del Duca D, et al. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. Cardiol Young 2007; 17(Suppl 2): 1–28.
• 2.   Ivemark BI. Implications of agenesis of the spleen on the pathogenesis of conotruncus anomalies in childhood: An analysis of the heart malformations in the splenic agenesis syndrome, with fourteen new cases. Acta Paediatr Suppl 1955; 44: 7–110.
• 3.   Moller JH, Nakib A, Anderson RC, Edwards JE. Congenital cardiac disease associated with polysplenia: A developmental complex of bilateral “left-sidedness”. Circulation 1967; 36: 789–799.
• 4.   Caruso G, Becker AE. How to determine atrial situs?: Considerations initiated by 3 cases of absent spleen with a discordant anatomy between bronchi and atria. Br Heart J 1979; 41: 559–567.
• 5.   Macartney FJ, Zuberbuhler JR, Anderson RH. Morphological considerations pertaining to recognition of atrial isomerism. Consequences for sequential chamber localisation. Br Heart J 1980; 44: 657–667.
• 6.   Uemura H, Ho SY, Devine WA, Anderson RH. Analysis of visceral heterotaxy according to splenic status, appendage morphology, or both. Am J Cardiol 1995; 76: 846–849.
• 7.   Shiraishi I, Ichikawa H. Human heterotaxy syndrome: From molecular genetics to clinical features, management, and prognosis. Circ J 2012; 76: 2066–2075.
• 8.   Phoon CK, Neill CA. Asplenia syndrome: Insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 1994; 73: 581–587.
• 9.   Peoples WM, Moller JH, Edwards JE. Polysplenia: A review of 146 cases. Pediatr Cardiol 1983; 4: 129–137.
• 10.   Bartz PJ, Driscoll DJ, Dearani JA, Puga FJ, Danielson GK, O’Leary PW, et al. Early and late results of the modified Fontan operation for heterotaxy syndrome: 30 years of experience in 142 patients. J Am Coll Cardiol 2006; 48: 2301–2305.
• 11.   Kothari SS. Non-cardiac issues in patients with heterotaxy syndrome. Ann Pediatr Cardiol 2014; 7: 187–192.
• 12.   Viswanathan S, Kumar RK. Assessment of operability of congenital cardiac shunts with increased pulmonary vascular resistance. Catheter Cardiovasc Interv 2008; 71: 665–670.
• 13.   Diller GP, Gatzoulis MA. Pulmonary vascular disease in adults with congenital heart disease. Circulation 2007; 115: 1039–1050.
• 14.   Steele PM, Fuster V, Cohen M, Ritter DG, McGoon DC. Isolated atrial septal defect with pulmonary vascular obstructive disease: Long-term follow-up and prediction of outcome after surgical correction. Circulation 1987; 76: 1037–1042.
• 15.   Loomba RS, Aggarwal S, Arora RR, Anderson R. Bodily isomerism is an independent risk factor for pulmonary hypertension in adults with congenital heart disease. Ther Adv Respir Dis 2016; 10: 194–199.
• 16.   Hoeper MM, Seyfarth HJ, Hoeffken G, Wirtz H, Spiekerkoetter E, Pletz MW, et al. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J 2007; 30: 1096–1102.
• 17.   Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel H. Pulmonary hypertension after splenectomy? Ann Intern Med 1999; 130: 506–509.
• 18.   Brandenburg VM, Krueger S, Haage P, Mertens P, Riehl J. Heterotaxy syndrome with severe pulmonary hypertension in an adult. South Med J 2002; 95: 536–538.
• 19.   Tanano H, Hasegawa T, Kawahara H, Sasaki T, Okada A. Biliary atresia associated with congenital structural anomalies. J Pediatr Surg 1999; 34: 1687–1690.
• 20.   Davenport M, Tizzard SA, Underhill J, Mieli-Vergani G, Portmann B, Hadzic N. The biliary atresia splenic malformation syndrome: A 28-year single-center retrospective study. J Pediatr 2006; 149: 393–400.
• 21.   Kobayashi D, Edwards HD, Singh J, Nadkarni MD, Lantz PE, Cook AL. Portopulmonary hypertension secondary to congenital extrahepatic portosystemic shunt with heterotaxy and polysplenia: A cause of sudden death in an infant. Pediatr Pulmonol 2011; 46: 1041–1044.
• 22.   Law YM, Mack CL, Sokol RJ, Rice M, Parsley L, Ivy D. Cardiopulmonary manifestations of portovenous shunts from congenital absence of the portal vein: Pulmonary hypertension and pulmonary vascular dilatation. Pediatr Transplant 2011; 15: E162–E168.
• 23.   Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30: 2493–2537.
• 24.   Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016; 37: 67–119.
• 25.   Bambul Heck P, Eicken A, Kasnar-Samprec J, Ewert P, Hager A. Early pulmonary arterial hypertension immediately after closure of a ventricular or complete atrioventricular septal defect beyond 6 months of age. Int J Cardiol 2017; 228: 313–318.
• 26.   Hazama K, Nakanishi T, Nakazawa M, Momma K. Pulmonary hypertension and pulmonary vascular obstructive disease in patients with polysplenia syndrome. J Pediatr Cardiol Cardiac Surg 1994; 10: 347–353.
• 27.   Goetschmann S, Dibernardo S, Steinmann H, Pavlovic M, Sekarski N, Pfammatter JP. Frequency of severe pulmonary hypertension complicating “isolated” atrial septal defect in infancy. Am J Cardiol 2008; 102: 340–342.
• 28.   Adatia I, Beghetti M. Immediate postoperative care. Cardiol Young 2009; 19(E-Suppl. 1): 23–27.
• 29.   Bartram U, Wirbelauer J, Speer CP. Heterotaxy syndrome: Asplenia and polysplenia as indicators of visceral malposition and complex congenital heart disease. Biol Neonate 2005; 88: 278–290.
• 30.   Burton EC, Olson M, Rooper L. Defects in laterality with emphasis on heterotaxy syndromes with asplenia and polysplenia: An autopsy case series at a single institution. Pediatr Dev Pathol 2014; 17: 250–264.
• 31.   Papagiannis J, Kanter RJ, Effman EL, Pratt PC, Arcille R, Browning IB, et al. Polysplenia with pulmonary arteriovenous malformations. Pediatr Cardiol 1993; 14: 127–129.
• 32.   McElhinney DB, Marx GR, Newburger JW. Congenital portosystemic venous connections and other abdominal venous abnormalities in patients with polysplenia and functionally univentricular heart disease: A case series and literature review. Congenit Heart Dis 2011; 6: 28–40.
• 33.   Schidlow DV, Katz SM, Turtz MG, Donner RM, Capasso S. Polysplenia and kartagener syndromes in a sibship: Association with abnormal respiratory cilia. J Pediatr 1982; 100: 401–403.
• 34.   Gershoni-Baruch R, Gottfried E, Pery M, Sahin A, Etzioni A. Immotile cilia syndrome including polysplenia, situs inversus, and extrahepatic biliary atresia. Am J Med Genet 1989; 33: 390–393.
• 35.   De Santis A, Morlupo M, Stati T, Lisi D, Pigna M, Antonelli M. Sonographic survey of the upper abdomen in 10 families of patients with immotile cilia syndrome. J Clin Ultrasound 1997; 25: 259–263.
• 36.   Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, et al. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation 2012; 125: 2232–2242.
• 37.   Klinger JR. The nitric oxide/cGMP signaling pathway in pulmonary hypertension. Clin Chest Med 2007; 28: 143–167, ix.
• 38.   Malinovschi A, Ludviksdottir D, Tufvesson E, Rolla G, Bjermer L, Alving K, et al. Application of nitric oxide measurements in clinical conditions beyond asthma. Eur Clin Respir J 2015; 2: 28517.
• 39.   Myers PO, Tissot C, Beghetti M. Assessment of operability of patients with pulmonary arterial hypertension associated with congenital heart disease: Do we have the good tools to predict success? Circ J 2014; 78: 4–11.