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Article Type: Review Articles Received Date: 10-Oct-2013• Revised Date: 13-Mar-2014 Accepted Date: 24-Mar-2014
Clinical Characteristics of Pulmonary Arterial Hypertension Associated with Down Syndrome1
Tsutomu Saji Department of Pediatrics, Pediatric Medical Center, Toho University Omori Medical Center, Tokyo, Japan
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ped.12349
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ABSTRACT The genetic abnormalities associated with Down syndrome (DS) are still being identified. Few studies have examined the roles of CRELD1 and GATA4 in cardiac abnormalities or their association with pulmonary artery histopathology. Children with DS have an elevated risk of pulmonary arterial hypertension (PAH). This increased risk is likely mainly due to genetic background, the structural characteristics of the pulmonary vascular wall, and certain heart diseases and partly due to pulmonary hypoplasia, upper and lower airway obstructive diseases, chronic infection, and neuromuscular underdevelopment. Exposure to increased left-to-right shunt flow increases sheer stress on endothelium and may induce endothelial dysfunction
followed by irreversible remodeling of pulmonary arteries.
Pathologic changes include endothelial cell proliferation and thickening of the pulmonary arterial wall due to mechanical responses to the thinner medial smooth muscle cell layer, which includes underdevelopment of alveoli. Production of prostacyclin and nitric oxide is diminished in DS, but levels of endothelin-1 and thromboxane are elevated. Perioperatively, 2 This article is protected by copyright. All rights reserved.
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patients with DS may experience pulmonary hypertensive crisis after intracardiac repair and prolonged PAH and have a poorer response to nitric oxide inhalation.
To better manage DS, it is crucial to systematically evaluate the systemic complications of DS. Cardiac catheterization data, particularly those regarding pulmonary arterial resistance, are essential in assessing severity and response to vasodilating agents, preventing postoperative crisis, and evaluating the possibility of intracardiac repair.
Advanced therapy with pulmonary vasodilating agents appears effective. Operative risk is similar for individuals with and without DS, except among patients with a complete atrioventricular canal defect.
Keywords: Down syndrome, pulmonary hypertension, congenital heart disease, atrioventricular septal defect, nitric oxide
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INTRODUCTION
Down syndrome (DS) was discovered in 1846 by Edouard Seguin, but it was the ophthalmologist Dr. Langdon Haydon Down (Fig. 1) who presented the paper "Observations on the Ethnic Classification of Idiots” at a conference in 1862. He referred to the syndrome as “Mongolism” due to the seemingly Mongoloid facial features of those who had the syndrome. Much later, in 1959, Lejeune discovered that the syndrome was associated with a trisomy at chromosome 21. The World Health Organization ultimately gave it its official name of Down syndrome in 1965.
DS is strongly associated with pulmonary arterial hypertension (PAH), although, interestingly, systemic arteriosclerosis is infrequent among individuals with DS (1, 2). There is also a high risk of Alzheimer disease, and the risk of developing leukemia is 20 times that of individuals without DS. In contrast, the incidences of breast cancer and solid tumors are lower among persons with DS.
Incidence of DS 4
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Recent studies have reported an incidence rate of DS is approximately 1 in 670-700 children (319-1000 children), and does not vary by race (3). DS is accompanied by congenital heart disease (CHD) in 40% to 50% of cases (4). CHD usually manifest in the atrioventricular canal as an atrioventricular septal defect (AVSD)in 60%, ventricular septal defect (VSD) in 20%, atrial septal defect (ASD) in 9% of cases, tetralogy of Fallot (T/F) in 7% of cases. It remains to be determined why there is virtually no dextrocardia or
transposition of the great arteries in persons with DS (5).
Cardiopulmonary Complications associated with DS I. The atrioventricular canal and AVSD DS is caused by chromosome 21 trisomy (Hsa21) at 21q22.3. DS is strongly correlated with abnormal atrioventricular valve formation. The mechanism underlying AVSD pathogenesis is related to abnormalities in the
cysteine-rich epidermal growth factor-like domain 1 (CRELD1) and GATA4 genes (6). CRELD1 is present throughout the human brain, and studies have identified it as a new adrenaline-receptor–binding protein (7). AVSDs are present in approximately 20% of persons with DS (8), and there seems to be a strong correlation between CRELD1 and incidence of AVSD in this 5 This article is protected by copyright. All rights reserved.
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population (9). CRELD1 is correlated with 3p-syndrome, which is a factor in AVSD pathogenesis. Some reports have implicated a microRNA gene.
Experimentally, many mouse models of DS exhibit cardiac abnormalities similar to those seen in humans with DS, and more than 100 different genes appear to be involved in regulating cardiac growth and development (10). There has been some interest in the MNB/DYRK1A gene, as it seems to be a powerful genetic factor in Alzheimer disease, endocytosis, and intracellular signaling. MNB/DYRK1A affects neuronal transmission and may lead to learning disabilities.
II. PAH
Studies of the correlation between DS and PAH have found abnormalities in various vasoactive substances. A study found that endothelin-1 (ET-1) and nitrate concentrations were higher in persons with DS than in those without DS, but not significantly so (11). When DS is accompanied by PAH, blood levels of arginine and nitric oxide products are lower, but the level of asymmetric dimethylarginine (ADMA) is increased, which has been reported as a possible reason for reduced nitric oxide production (12). However, in the endothelial nitric oxide synthase (eNOS) variant of DS, there is no 6
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difference in these levels as compared with individuals without DS (13).
When DS patients are removed from cardiopulmonary bypass, elevation of blood ET-1 significantly prolonged to normalize, and the elevation tends to
persist (14). Postoperatively, patients with DS and PAH had a poorer response to NO inhalation (15). Patients with idiopathic PAH have high blood levels of epinephrine, but levels are actually lower than normal in persons with DS, an apparent contradiction (16). Among patients with DS and CHD with left to right shunt, the prostacyclin (PGI2)/thromboxane (TXB2) ratio was significantly lower, with reduced production of PGI2 and significantly increased production of TXB2, which increased platelet aggregation, cell proliferation, and vasoconstriction, thereby potentially increasing PAH histological severity (17, 18).
Pathology of the DS–PAH connection In general, among individuals with an ASD of the same size, persons with
DS will develop PAH more quickly and demonstrate greater damage to the pulmonary vascular bed. These findings regarding DS patients were already being reported in the 1970s (19). In 1976, Chi began investigating the
relationship between DS and the pulmonary vascular bed. 7 This article is protected by copyright. All rights reserved.
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In Japan, the leading researcher of the pathology of PAH was Dr. Shigeo Yamaki. His longtime research and observation revealed that surgery was indicated when DS patients with a VSD had an index of pulmonary vascular disease (IPVD) of ≤2.2. When a patient with a VSD did not have DS, the recommended IPVD was ≤2.1 (20). According to Yamaki, when pulmonary vascular resistance (PVR) is ≥8 units or ≥4 as a result of acute vasodilating test such as 100% oxygen inhalation, the decision to proceed with surgery should be based on lung biopsy findings. However, in patients with DS or
transposition of the great arteries (TGA) resulting from insufficient development of vascular smooth muscle cells, even among those with high pulmonary artery pressure, no thickening of the tunica media develops in response to this pressure, which then results in early development of intimal thickening (21). In other words, because there is insufficient thickening of the tunica media in response to high PVR, the shear stress per unit of surface area is higher, and, as indicated by the Laplace theorem, intimal thickening develops in response. This theory was developed by Yamaki to explain the above observations. Furthermore, in DS, wedge angiographies reveal abnormally small numbers of branches and capillaries leading from 8 This article is protected by copyright. All rights reserved.
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the pulmonary artery, with little tortuosity of the vessel (22).
In clinical practice, DS is associated with small-caliber blood vessels.
Peripheral vessels are especially fine, and great variation in the capillaries of nail beds appears characteristic of DS. This phenomenon seems to worsen with age, and in addition to the pulmonary vasculature, capillaries throughout the body are affected (23). Although there is some inconsistency between pathological findings of a poor thickening of the tunica media and intimal thickening in PAH, normal development and functional capacity of SMC in DS may be absent.
Clinical observations of PAH in DS In newborns with DS, PAH usually persists unabated, and the period required for an increase in the volume of left-to-right cardiac shunting is prolonged, which must be taken into account when considering the timing of pulmonary artery banding (Table 1). In comparison with other cases of general CHD, infants with DS have larger AVSDs and a disproportionately high rate of PAH for their age (24). In other words, PAH is more frequent (25,
26) and develops earlier in this population (27). Among patients with AVSD, 9
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there is a high rate of PAH (28) and, as in cases in which left atrial pressure
or pulmonary venous pressure is high, there is a high risk of postoperative
PAH crisis (29). Some studies reported no difference in PAH incidence between patients with
and without DS. In other words, although PAH can easily develop in DS patients with AVSD (30), there are generally no significant differences between individuals with and without DS with respect to hemodynamics, ie, PAH severity, Rp severity in PVR, and response to oxygen (31).
Overall, 45% of individuals with Eisenmenger Syndrome have DS (32), and it is suspected that individual risk factors such as elevated brain natriuretic peptide (BNP), reduced 6-min walk test (6MWT), and renal dysfunction influence prognosis in many cases (33). In examination of 6MWT among people with DS, no significant difference was noted between participants
with and without CHD, but this finding may have been influenced by the participants' ages, female sex, and low IQ (34).
Approximately 30% of adults with CHD accompanied by ASD, VSD or AVSD, have DS, and mortality is high among this population (OR, 2.9) (35). 10
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Factors associated with more severe PAH among individuals with DS:
Respiratory diseases DS is often accompanied by a variety of complications and associated conditions (Fig. 2), many of which are closely associated with factors that worsen PAH (5).
Among DS patients with CHD, 6.9% have gastrointestinal complications and 1.8% have abnormalities of the urinary tract and reproductive system. The American Pediatric Association has published a report on Health Supervision for Children With Down Syndrome (2001), which highlights the necessity of echocardiograms of the fetus and newborn (before age 2 months) in all DS patients (36).
Respiratory abnormalities are frequent in DS. Pulmonary hypoplasia
decreases the number of alveoli, and individual alveoli tend to be enlarged (37). Thus, the surface area of alveoli that can be covered by capillaries is
proportionately smaller, and PAH develops more easily. Respiratory 11 This article is protected by copyright. All rights reserved.
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abnormalities might be caused by the presence of abnormal substances in amniotic fluid, which is then absorbed into the lungs during fetal breathing. Alveolar hypoplasia and emphysema-like lesions were described by Yamaki et al: interstitial emphysema, enlarged peripheral airways, and hypoplasia
of the alveoli walls are all present. A study reported finding fewer than half
the normal number of elastic fibers in the alveolar wall (38). In addition, DS
is often associated with chronic upper respiratory tract obstruction, enlarged adenoids, macroglossia, glossoptosis, laryngomalacia, sleep apnea syndrome (39), mid-facial hypoplasia, reduced muscle tone,
hypoventilation, complications involving aspiration pneumonia (40), abnormal aryepiglottic folds, esophagobronchial fistulae, and plexogenic arteriopathies in the pulmonary blood vessels (41). Alveolar capillary dysplasia is also often present, as is pulmonary edema on level ground and in other high altitude areas (42). Another study reported Cheyne-Stokes
respiration and pulmonary embolism accompanying transient abnormal myolopoiesis (TAM) (43). These factors, together with hypoxia, hypercapnia, and alveolar hypoventilation, may promote PAH development. For this reason, individuals with DS and respiratory disabilities should undergo overnight polysomnographic testing. Special attention is warranted if sleep 12 This article is protected by copyright. All rights reserved.
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apnea syndrome (SAS) symptoms do not improve, even after surgical
removal of adenoids, in cases with other potential obstructions of the upper respiratory tract such as in overweight patients or those with marked
midfacial hypoplasia, or if complications involving neurologic disorders are present (44). PAH may also be worsened by chronic inflammation of the lower respiratory tract and tracheal spasms accompanying gastroesophageal reflux. Fistulae can appear in the portal vein or hepatic
artery, and portal vein-related PAHmay also develop (45). Severe PAH is a concern when pulmonary complications develop in patients younger than 1 year (46). Bone abnormalities in the chest wall, such as vertebral hypoplasia or complete absence of the 12th rib, have also been observed (47).
Incidence and severity of bronchiolitis are greater among DS patients infected with respiratory syncytial virus (RSV). Because the airways of DS patients with PAH are usually obstructed by the dilated pulmonary artery, and pulmonary alveoli are already enlarged, people with DS must be protected from RSV infection (48, 49), as such infection can result in acute
lung injury and/or acute respiratory distress syndrome. These respiratory abnormalities are important factors in the development and progression of 13 This article is protected by copyright. All rights reserved.
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PAH. Therefore, pediatricians must be prepared to identify and manage such variety of complications.
DS and persistent pulmonary hypertension of the newborn The incidence rate of persistent pulmonary hypertension of the newborn (PPHN) is particularly high in DS (1.2-5.2%) (50-52). Endothelial nitric oxide synthase, angiotensin-converting enzyme, and the angiotensin II type 1 receptor seem to have important roles in pathogenesis of PPHN, as does BMPR2 in some cases (53). A recent study found that a genetic variant of mitochondrial carbamoyl-phosphate synthetase 1 (CPS1) was associated with PPHN, and that this CPS1 variant might also induce postoperative PAH (54).
Is DS a risk factor for postoperative PAH? Cardiac catheterization data and pulmonary artery wedge angiograms from DS patients with intra cardiac shunt showed no significant difference
between them and participants without DS with respect to responsiveness
to oxygenation (31). In addition, the risks and outcomes after open heart surgery were similar among patients with and without DS (55-57); however, 14 This article is protected by copyright. All rights reserved.
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the mortality rate for DS patients was lower, as was the incidence rate of severe valvular regurgitation. DS patients did have a higher risk of infection (58).
Infants with DS and Rastelli type A AVSDs had a higher risk of PAH, and there is general agreement that the risk remains elevated even after age 1 year, although 1 study found that such patients actually had better results (59). The incidence and severity of PAH did not significantly differ among patients with Rastelli type C AVSDs, as compared with people without DS
(60, 61). A study of lung biopsy results for patients with PAH and pulmonary artery banding reported greater histologic improvements and better prognoses when 2-stage surgical procedures were selected (62)
Some studies reported delayed recovery of left ventricular function (LVSW/EDV) (63) and increased need for NO inhalation after VSD surgery (64). The time required for safe postoperative extubation was longer among
patients with DS (65) and, as with other PAH complications, it was more difficult for early extubation (66). In DS patients with univentricular hearts, atrioventricular valve regurgitation and PAH increase the risk of bidirectional 15 This article is protected by copyright. All rights reserved.
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cavopulmonary shunt procedures (67). In cases of heart transplantation for DS, postoperative complications were more frequent. In addition, malignancies due to immunosuppressive agents , as were rates of post-transplant lymphoproliferative disorder like PTLD were also observed among DS patients (68). Moreover, significant number of patients with
Down syndrome demonstrate episodic atrioventricular block in early and late follow-up period (69). Risk factors of developing PAH in Down syndrome are shown in Table 2.
Response to PAH medications Individuals with DS make up almost half the total population of Eisenmenger’s syndrome patients (aaa). But treatment by sildenafil, bosentan or ambrisentan for DS with PAH or with Eisenmenger’s syndrome has not been fully investigated. There are no randomized controlled trials in DS with PAH or with Eisenenger’s syndrome (73, bbb). Most studies suggest that the bosentan endothelin receptor antagonist is almost equally effective for PAH in patients with and without DS (70-72). Bosentan has acute vasodilative effects as well as chronic effects such as anti-proliferative effects , anti-fibrotic effects, and anti-inflammatory effects (ddd) for 16 This article is protected by copyright. All rights reserved.
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reverse remodeling. A few reports found that, as compared with patients without DS, those with DS had less recovery in examining 6MWD and scores on the Medical Outcomes Study Short Form 36 General Health Survey (73).
Another study found no differences in the efficacy of bosentan between PAH with CHD in patients with or without DS (72). One study reported that so-called disease-targeting therapy was effective for patients with Eisenmenger syndrome accompanied by DS (74). In DS, it is difficult to judge the effectiveness of pulmonary vasodilative agents by evaluating primary end-point such as 6 minutes walking distance or NYHA functional class because of their lower intelligence (ccc). Conclusion
Although there is no consensus on the risk of pulmonary arterial hypertension (PAH) associated with an atrioventricular septal defect, it is unclear whether surgical outcomes are similar for patients with and without DS when clinicians are unaware of the optimal timing for clinical assessment of DS patients, the various risk factors for more severe PAH, or the suitable treatments for such patients. In DS-specific general hypoplasia of the respiratory system, histologic analysis may yield findings similar to those of 17
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emphysema, the vascular wall may easily thicken in response to increased shear stress, and there is the risk that these abnormalities may progress to secondary PAH or PAH complications. Discoveries concerning DS continue to be made 150 years after its discovery and 50 years after the chromosomal abnormality responsible was identified. Clinical applications based on these results continue to improve the lives of those affected by DS.
This article is based on a study first reported in Pediatric Cardiology and Cardiac Surgery, 2013; 29: 3-10 (75).
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response to inhaled nitric oxide. Scand Cardiovasc J. 2000; 4: 46-52 [65] Ip P, Chiu CS, Cheung YF et al: Risk factors prolonging ventilation in young children after cardiac surgery: Impact of noninfectious pulmonary complications. Pediatri Crit Care Med. 2002;3:269-274 [66] Harrison AM, Cox AC, Davis ,et al: Failed extubation after cardiac surgery in young children: Prevalence, pathigenesis, and risk factors. Pediatr Crit Care Med. 2002;3:148-152 [67] Wada N, Takahashi Y, Ando M, et al: Single ventricle repair in children with Down’s syndrome. Gen Thorac Cardiovasc Surg 2008;56:104-108,
[68] Leonard H, Eastham K, Dark J: Heart and Lung transplantation in Down’s syndrome. BMJ 2000; 320:816-817 [69] Banks MA, Jenson J, Kugler JD. Late development of atrioventricular block after congenital heart surgery in Down syndrome. Am J Cardiol 2001;88:A7,86-89
[70] Dufflels MG, Vis JC, van Loon RL, et a: Down patients with Eisemnmenger syndrome: is bosentan treatment an option?
Int J Cardiol
2009;134:378-383 [71] Kermeen FD, Franks C, O’brien K, et al: Endothelin receptor antagonists are an effective long term treatment option in pulmonary 29
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arterial hypertension associated with congenital heart disease with or without trisomy 21. Heart Lung Circ. 2010;19:595-600 [72] D’Alto M, Romeo E, Argiento P,et al: Therapy for pulmonary hypertension due to congenital heart disease and Down’s syndrome. Int J Cariol. 2011 (Epub ahead of print)
[73] Duffels MGJ, Vis JC, van Loon RLE, et al: Effect of Bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenitaln heart disease with and without Down’s syndrome. Am J cardiol 2009;103: 1309-1315 [74] Diller GP, Alonso-Gonalez R, Dimopoulos K, et al: Disease targeting therapies in patients with Eisenmenger syndrome: response to treatment and long-term efficacy. Int J Cardiol. 2012 (Epub ahead of print) [75] Saji T: Clinical Characteristics of pulmonary arterial hypertension
associated with Down syndrome. Pediatric Cardiology and Cardiac Surgery. 2013; 29:3-10 [aaa]. Van de Bruaene A, Delcroix M, Pasquet A, et al: The Belgian Eisenmenger syndrome registry: implications for treatment strategies? Acta Cardiol. 2009; 64: 447–453.
[bbb]. Kaya MG, Lam YY, Erer B, et al: Long-term effect of bosentan therapy on cardiac function and symptomatic benefits in adult patients with 30 This article is protected by copyright. All rights reserved.
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Eisenmenger syndrome. J Card Fail. 2012; 18: 379-384. [ccc]. D'Alto M, ,Mahadevan MS: Pulmonary arterial hypertension associated with congenital heart disease. Eur Respir Rev. 2012; 126 328-337.
[ddd]. Boniface S, Reynaud-Gaubert M: Endothelin receptor antagonists-their role in pulmonary medicine. Rev Mal Respir. 2011, 8:e94-e107
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Table 1. Risk of Severe Pulmonary Vasculopathy Associated with Specific Congenital Heart Disease (24)
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Table 2. Factors contributing to PAH incidence and progression in Down syndrome. 1) 2) 3) 4)
Congenital heart diseases (ADSD>>PDA>VSD>ASD) Sleep apnea syndrome Emphysema after RSV infection Recurrent lower respiratory infection
5) Low birth weight 6) TAM 7) Factors associated with hypoxia
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FIGURE LEGENDS
Figure 1. John Langdon HAYDON Down
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Figure 2. Systemic complications in Down syndrome
Article Type: Review Articles Received Date: 10-Oct-2013• Revised Date: 13-Mar-2014 Accepted Date: 24-Mar-2014
Clinical Characteristics of Pulmonary Arterial Hypertension Associated with Down Syndrome1
Tsutomu Saji Department of Pediatrics, Pediatric Medical Center, Toho University Omori Medical Center, Tokyo, Japan
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ped.12349
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ABSTRACT The genetic abnormalities associated with Down syndrome (DS) are still being identified. Few studies have examined the roles of CRELD1 and GATA4 in cardiac abnormalities or their association with pulmonary artery histopathology. Children with DS have an elevated risk of pulmonary arterial hypertension (PAH). This increased risk is likely mainly due to genetic background, the structural characteristics of the pulmonary vascular wall, and certain heart diseases and partly due to pulmonary hypoplasia, upper and lower airway obstructive diseases, chronic infection, and neuromuscular underdevelopment. Exposure to increased left-to-right shunt flow increases sheer stress on endothelium and may induce endothelial dysfunction
followed by irreversible remodeling of pulmonary arteries.
Pathologic changes include endothelial cell proliferation and thickening of the pulmonary arterial wall due to mechanical responses to the thinner medial smooth muscle cell layer, which includes underdevelopment of alveoli. Production of prostacyclin and nitric oxide is diminished in DS, but levels of endothelin-1 and thromboxane are elevated. Perioperatively, 2 This article is protected by copyright. All rights reserved.
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patients with DS may experience pulmonary hypertensive crisis after intracardiac repair and prolonged PAH and have a poorer response to nitric oxide inhalation.
To better manage DS, it is crucial to systematically evaluate the systemic complications of DS. Cardiac catheterization data, particularly those regarding pulmonary arterial resistance, are essential in assessing severity and response to vasodilating agents, preventing postoperative crisis, and evaluating the possibility of intracardiac repair.
Advanced therapy with pulmonary vasodilating agents appears effective. Operative risk is similar for individuals with and without DS, except among patients with a complete atrioventricular canal defect.
Keywords: Down syndrome, pulmonary hypertension, congenital heart disease, atrioventricular septal defect, nitric oxide
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INTRODUCTION
Down syndrome (DS) was discovered in 1846 by Edouard Seguin, but it was the ophthalmologist Dr. Langdon Haydon Down (Fig. 1) who presented the paper "Observations on the Ethnic Classification of Idiots” at a conference in 1862. He referred to the syndrome as “Mongolism” due to the seemingly Mongoloid facial features of those who had the syndrome. Much later, in 1959, Lejeune discovered that the syndrome was associated with a trisomy at chromosome 21. The World Health Organization ultimately gave it its official name of Down syndrome in 1965.
DS is strongly associated with pulmonary arterial hypertension (PAH), although, interestingly, systemic arteriosclerosis is infrequent among individuals with DS (1, 2). There is also a high risk of Alzheimer disease, and the risk of developing leukemia is 20 times that of individuals without DS. In contrast, the incidences of breast cancer and solid tumors are lower among persons with DS.
Incidence of DS 4
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Recent studies have reported an incidence rate of DS is approximately 1 in 670-700 children (319-1000 children), and does not vary by race (3). DS is accompanied by congenital heart disease (CHD) in 40% to 50% of cases (4). CHD usually manifest in the atrioventricular canal as an atrioventricular septal defect (AVSD)in 60%, ventricular septal defect (VSD) in 20%, atrial septal defect (ASD) in 9% of cases, tetralogy of Fallot (T/F) in 7% of cases. It remains to be determined why there is virtually no dextrocardia or
transposition of the great arteries in persons with DS (5).
Cardiopulmonary Complications associated with DS I. The atrioventricular canal and AVSD DS is caused by chromosome 21 trisomy (Hsa21) at 21q22.3. DS is strongly correlated with abnormal atrioventricular valve formation. The mechanism underlying AVSD pathogenesis is related to abnormalities in the
cysteine-rich epidermal growth factor-like domain 1 (CRELD1) and GATA4 genes (6). CRELD1 is present throughout the human brain, and studies have identified it as a new adrenaline-receptor–binding protein (7). AVSDs are present in approximately 20% of persons with DS (8), and there seems to be a strong correlation between CRELD1 and incidence of AVSD in this 5 This article is protected by copyright. All rights reserved.
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population (9). CRELD1 is correlated with 3p-syndrome, which is a factor in AVSD pathogenesis. Some reports have implicated a microRNA gene.
Experimentally, many mouse models of DS exhibit cardiac abnormalities similar to those seen in humans with DS, and more than 100 different genes appear to be involved in regulating cardiac growth and development (10). There has been some interest in the MNB/DYRK1A gene, as it seems to be a powerful genetic factor in Alzheimer disease, endocytosis, and intracellular signaling. MNB/DYRK1A affects neuronal transmission and may lead to learning disabilities.
II. PAH
Studies of the correlation between DS and PAH have found abnormalities in various vasoactive substances. A study found that endothelin-1 (ET-1) and nitrate concentrations were higher in persons with DS than in those without DS, but not significantly so (11). When DS is accompanied by PAH, blood levels of arginine and nitric oxide products are lower, but the level of asymmetric dimethylarginine (ADMA) is increased, which has been reported as a possible reason for reduced nitric oxide production (12). However, in the endothelial nitric oxide synthase (eNOS) variant of DS, there is no 6
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difference in these levels as compared with individuals without DS (13).
When DS patients are removed from cardiopulmonary bypass, elevation of blood ET-1 significantly prolonged to normalize, and the elevation tends to
persist (14). Postoperatively, patients with DS and PAH had a poorer response to NO inhalation (15). Patients with idiopathic PAH have high blood levels of epinephrine, but levels are actually lower than normal in persons with DS, an apparent contradiction (16). Among patients with DS and CHD with left to right shunt, the prostacyclin (PGI2)/thromboxane (TXB2) ratio was significantly lower, with reduced production of PGI2 and significantly increased production of TXB2, which increased platelet aggregation, cell proliferation, and vasoconstriction, thereby potentially increasing PAH histological severity (17, 18).
Pathology of the DS–PAH connection In general, among individuals with an ASD of the same size, persons with
DS will develop PAH more quickly and demonstrate greater damage to the pulmonary vascular bed. These findings regarding DS patients were already being reported in the 1970s (19). In 1976, Chi began investigating the
relationship between DS and the pulmonary vascular bed. 7 This article is protected by copyright. All rights reserved.
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In Japan, the leading researcher of the pathology of PAH was Dr. Shigeo Yamaki. His longtime research and observation revealed that surgery was indicated when DS patients with a VSD had an index of pulmonary vascular disease (IPVD) of ≤2.2. When a patient with a VSD did not have DS, the recommended IPVD was ≤2.1 (20). According to Yamaki, when pulmonary vascular resistance (PVR) is ≥8 units or ≥4 as a result of acute vasodilating test such as 100% oxygen inhalation, the decision to proceed with surgery should be based on lung biopsy findings. However, in patients with DS or
transposition of the great arteries (TGA) resulting from insufficient development of vascular smooth muscle cells, even among those with high pulmonary artery pressure, no thickening of the tunica media develops in response to this pressure, which then results in early development of intimal thickening (21). In other words, because there is insufficient thickening of the tunica media in response to high PVR, the shear stress per unit of surface area is higher, and, as indicated by the Laplace theorem, intimal thickening develops in response. This theory was developed by Yamaki to explain the above observations. Furthermore, in DS, wedge angiographies reveal abnormally small numbers of branches and capillaries leading from 8 This article is protected by copyright. All rights reserved.
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the pulmonary artery, with little tortuosity of the vessel (22).
In clinical practice, DS is associated with small-caliber blood vessels.
Peripheral vessels are especially fine, and great variation in the capillaries of nail beds appears characteristic of DS. This phenomenon seems to worsen with age, and in addition to the pulmonary vasculature, capillaries throughout the body are affected (23). Although there is some inconsistency between pathological findings of a poor thickening of the tunica media and intimal thickening in PAH, normal development and functional capacity of SMC in DS may be absent.
Clinical observations of PAH in DS In newborns with DS, PAH usually persists unabated, and the period required for an increase in the volume of left-to-right cardiac shunting is prolonged, which must be taken into account when considering the timing of pulmonary artery banding (Table 1). In comparison with other cases of general CHD, infants with DS have larger AVSDs and a disproportionately high rate of PAH for their age (24). In other words, PAH is more frequent (25,
26) and develops earlier in this population (27). Among patients with AVSD, 9
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there is a high rate of PAH (28) and, as in cases in which left atrial pressure
or pulmonary venous pressure is high, there is a high risk of postoperative
PAH crisis (29). Some studies reported no difference in PAH incidence between patients with
and without DS. In other words, although PAH can easily develop in DS patients with AVSD (30), there are generally no significant differences between individuals with and without DS with respect to hemodynamics, ie, PAH severity, Rp severity in PVR, and response to oxygen (31).
Overall, 45% of individuals with Eisenmenger Syndrome have DS (32), and it is suspected that individual risk factors such as elevated brain natriuretic peptide (BNP), reduced 6-min walk test (6MWT), and renal dysfunction influence prognosis in many cases (33). In examination of 6MWT among people with DS, no significant difference was noted between participants
with and without CHD, but this finding may have been influenced by the participants' ages, female sex, and low IQ (34).
Approximately 30% of adults with CHD accompanied by ASD, VSD or AVSD, have DS, and mortality is high among this population (OR, 2.9) (35). 10
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Factors associated with more severe PAH among individuals with DS:
Respiratory diseases DS is often accompanied by a variety of complications and associated conditions (Fig. 2), many of which are closely associated with factors that worsen PAH (5).
Among DS patients with CHD, 6.9% have gastrointestinal complications and 1.8% have abnormalities of the urinary tract and reproductive system. The American Pediatric Association has published a report on Health Supervision for Children With Down Syndrome (2001), which highlights the necessity of echocardiograms of the fetus and newborn (before age 2 months) in all DS patients (36).
Respiratory abnormalities are frequent in DS. Pulmonary hypoplasia
decreases the number of alveoli, and individual alveoli tend to be enlarged (37). Thus, the surface area of alveoli that can be covered by capillaries is
proportionately smaller, and PAH develops more easily. Respiratory 11 This article is protected by copyright. All rights reserved.
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abnormalities might be caused by the presence of abnormal substances in amniotic fluid, which is then absorbed into the lungs during fetal breathing. Alveolar hypoplasia and emphysema-like lesions were described by Yamaki et al: interstitial emphysema, enlarged peripheral airways, and hypoplasia
of the alveoli walls are all present. A study reported finding fewer than half
the normal number of elastic fibers in the alveolar wall (38). In addition, DS
is often associated with chronic upper respiratory tract obstruction, enlarged adenoids, macroglossia, glossoptosis, laryngomalacia, sleep apnea syndrome (39), mid-facial hypoplasia, reduced muscle tone,
hypoventilation, complications involving aspiration pneumonia (40), abnormal aryepiglottic folds, esophagobronchial fistulae, and plexogenic arteriopathies in the pulmonary blood vessels (41). Alveolar capillary dysplasia is also often present, as is pulmonary edema on level ground and in other high altitude areas (42). Another study reported Cheyne-Stokes
respiration and pulmonary embolism accompanying transient abnormal myolopoiesis (TAM) (43). These factors, together with hypoxia, hypercapnia, and alveolar hypoventilation, may promote PAH development. For this reason, individuals with DS and respiratory disabilities should undergo overnight polysomnographic testing. Special attention is warranted if sleep 12 This article is protected by copyright. All rights reserved.
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apnea syndrome (SAS) symptoms do not improve, even after surgical
removal of adenoids, in cases with other potential obstructions of the upper respiratory tract such as in overweight patients or those with marked
midfacial hypoplasia, or if complications involving neurologic disorders are present (44). PAH may also be worsened by chronic inflammation of the lower respiratory tract and tracheal spasms accompanying gastroesophageal reflux. Fistulae can appear in the portal vein or hepatic
artery, and portal vein-related PAHmay also develop (45). Severe PAH is a concern when pulmonary complications develop in patients younger than 1 year (46). Bone abnormalities in the chest wall, such as vertebral hypoplasia or complete absence of the 12th rib, have also been observed (47).
Incidence and severity of bronchiolitis are greater among DS patients infected with respiratory syncytial virus (RSV). Because the airways of DS patients with PAH are usually obstructed by the dilated pulmonary artery, and pulmonary alveoli are already enlarged, people with DS must be protected from RSV infection (48, 49), as such infection can result in acute
lung injury and/or acute respiratory distress syndrome. These respiratory abnormalities are important factors in the development and progression of 13 This article is protected by copyright. All rights reserved.
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PAH. Therefore, pediatricians must be prepared to identify and manage such variety of complications.
DS and persistent pulmonary hypertension of the newborn The incidence rate of persistent pulmonary hypertension of the newborn (PPHN) is particularly high in DS (1.2-5.2%) (50-52). Endothelial nitric oxide synthase, angiotensin-converting enzyme, and the angiotensin II type 1 receptor seem to have important roles in pathogenesis of PPHN, as does BMPR2 in some cases (53). A recent study found that a genetic variant of mitochondrial carbamoyl-phosphate synthetase 1 (CPS1) was associated with PPHN, and that this CPS1 variant might also induce postoperative PAH (54).
Is DS a risk factor for postoperative PAH? Cardiac catheterization data and pulmonary artery wedge angiograms from DS patients with intra cardiac shunt showed no significant difference
between them and participants without DS with respect to responsiveness
to oxygenation (31). In addition, the risks and outcomes after open heart surgery were similar among patients with and without DS (55-57); however, 14 This article is protected by copyright. All rights reserved.
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the mortality rate for DS patients was lower, as was the incidence rate of severe valvular regurgitation. DS patients did have a higher risk of infection (58).
Infants with DS and Rastelli type A AVSDs had a higher risk of PAH, and there is general agreement that the risk remains elevated even after age 1 year, although 1 study found that such patients actually had better results (59). The incidence and severity of PAH did not significantly differ among patients with Rastelli type C AVSDs, as compared with people without DS
(60, 61). A study of lung biopsy results for patients with PAH and pulmonary artery banding reported greater histologic improvements and better prognoses when 2-stage surgical procedures were selected (62)
Some studies reported delayed recovery of left ventricular function (LVSW/EDV) (63) and increased need for NO inhalation after VSD surgery (64). The time required for safe postoperative extubation was longer among
patients with DS (65) and, as with other PAH complications, it was more difficult for early extubation (66). In DS patients with univentricular hearts, atrioventricular valve regurgitation and PAH increase the risk of bidirectional 15 This article is protected by copyright. All rights reserved.
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cavopulmonary shunt procedures (67). In cases of heart transplantation for DS, postoperative complications were more frequent. In addition, malignancies due to immunosuppressive agents , as were rates of post-transplant lymphoproliferative disorder like PTLD were also observed among DS patients (68). Moreover, significant number of patients with
Down syndrome demonstrate episodic atrioventricular block in early and late follow-up period (69). Risk factors of developing PAH in Down syndrome are shown in Table 2.
Response to PAH medications Individuals with DS make up almost half the total population of Eisenmenger’s syndrome patients (aaa). But treatment by sildenafil, bosentan or ambrisentan for DS with PAH or with Eisenmenger’s syndrome has not been fully investigated. There are no randomized controlled trials in DS with PAH or with Eisenenger’s syndrome (73, bbb). Most studies suggest that the bosentan endothelin receptor antagonist is almost equally effective for PAH in patients with and without DS (70-72). Bosentan has acute vasodilative effects as well as chronic effects such as anti-proliferative effects , anti-fibrotic effects, and anti-inflammatory effects (ddd) for 16 This article is protected by copyright. All rights reserved.
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reverse remodeling. A few reports found that, as compared with patients without DS, those with DS had less recovery in examining 6MWD and scores on the Medical Outcomes Study Short Form 36 General Health Survey (73).
Another study found no differences in the efficacy of bosentan between PAH with CHD in patients with or without DS (72). One study reported that so-called disease-targeting therapy was effective for patients with Eisenmenger syndrome accompanied by DS (74). In DS, it is difficult to judge the effectiveness of pulmonary vasodilative agents by evaluating primary end-point such as 6 minutes walking distance or NYHA functional class because of their lower intelligence (ccc). Conclusion
Although there is no consensus on the risk of pulmonary arterial hypertension (PAH) associated with an atrioventricular septal defect, it is unclear whether surgical outcomes are similar for patients with and without DS when clinicians are unaware of the optimal timing for clinical assessment of DS patients, the various risk factors for more severe PAH, or the suitable treatments for such patients. In DS-specific general hypoplasia of the respiratory system, histologic analysis may yield findings similar to those of 17
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emphysema, the vascular wall may easily thicken in response to increased shear stress, and there is the risk that these abnormalities may progress to secondary PAH or PAH complications. Discoveries concerning DS continue to be made 150 years after its discovery and 50 years after the chromosomal abnormality responsible was identified. Clinical applications based on these results continue to improve the lives of those affected by DS.
This article is based on a study first reported in Pediatric Cardiology and Cardiac Surgery, 2013; 29: 3-10 (75).
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arterial hypertension associated with congenital heart disease with or without trisomy 21. Heart Lung Circ. 2010;19:595-600 [72] D’Alto M, Romeo E, Argiento P,et al: Therapy for pulmonary hypertension due to congenital heart disease and Down’s syndrome. Int J Cariol. 2011 (Epub ahead of print)
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31 This article is protected by copyright. All rights reserved.
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Table 1. Risk of Severe Pulmonary Vasculopathy Associated with Specific Congenital Heart Disease (24)
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Table 2. Factors contributing to PAH incidence and progression in Down syndrome. 1) 2) 3) 4)
Congenital heart diseases (ADSD>>PDA>VSD>ASD) Sleep apnea syndrome Emphysema after RSV infection Recurrent lower respiratory infection
5) Low birth weight 6) TAM 7) Factors associated with hypoxia
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FIGURE LEGENDS
Figure 1. John Langdon HAYDON Down
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Figure 2. Systemic complications in Down syndrome
