International Journal of Cardiology 174 (2014) 299–305
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Contemporary prevalence of pulmonary arterial hypertension in adult congenital heart disease following the updated clinical classiﬁcation Annelieke C.M.J. van Riel a,b,1, Mark J. Schuuring a,1, Irene D. van Hessen a,1, Aielko H. Zwinderman c,1, Luc Cozijnsen d,1, Constant L.A. Reichert e,1, Jan C.A. Hoorntje f,1, Lodewijk J. Wagenaar g,1, Marco C. Post h,1, Arie P.J. van Dijk i,1, Elke S. Hoendermis j,1, Barbara J.M. Mulder a,b,1, Berto J. Bouma a,⁎,1 a
Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands c Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, Amsterdam d Department of Cardiology, Gelre Hospital, Apeldoorn, The Netherlands e Department of Cardiology, Medical Centre Alkmaar, Alkmaar, The Netherlands f Department of Cardiology, Isala Klinieken, Zwolle, The Netherlands g Department of Cardiology, Medisch Spectrum Twente Hospital, Enschede, The Netherlands h Department of Cardiology, St Antonius Hospital, Nieuwegein, The Netherlands i Department of Cardiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands j Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands b
a r t i c l e
i n f o
Article history: Received 6 December 2013 Received in revised form 6 March 2014 Accepted 4 April 2014 Available online 16 April 2014 Keywords: Epidemiology Prevalence Pulmonary arterial hypertension Adult congenital heart disease Echocardiography
a b s t r a c t Background: The aging congenital heart disease (CHD) population is prone to develop a variety of sequelae, including pulmonary arterial hypertension (PAH). Previous prevalence estimates are limited in applicability due to the use of tertiary centers, or database encoding only. We aimed to investigate the contemporary prevalence of PAH in adult CHD patients, using a nationwide population. Methods: A cross-sectional study was performed, using the population-based Dutch CONgenital CORvitia (CONCOR) registry. All patients born with a systemic-to-pulmonary shunt, thereby at risk of developing PAH, were identiﬁed. From this cohort, a random sample was obtained and carefully reviewed. Results: Of 12,624 registered adults with CHD alive in 2011, 5,487 (44%) were at risk of PAH. The random sample consisted of 1,814 patients (mean age 40 ± 15 years) and 135 PAH cases were observed. PAH prevalence in patients born with a systemic-to-pulmonary shunt was 7.4%. The prevalence of PAH after corrective cardiac surgery was remarkably high (5.7%). Furthermore, PAH prevalence increased with age, from 2.5% under 30 years until 35% in the eldest. PAH prevalence in the entire CHD population was 3.2%. Based on 3000 per million adult CHD patients in the general population, we can assume that PAH-CHD is present in 100 per million. Conclusions: This new approach using a nationwide CHD population reports a PAH prevalence of 3.2% in CHD patients, and 100 per million in the general adult population. Especially in patients after shunt closure and the elderly, physicians should be aware of PAH-CHD, to provide optimal therapeutic and clinical care. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary arterial hypertension (PAH) is a well-known complication in congenital heart disease (CHD) limiting functional capacity and survival in these patients [1–4]. During the past decades, advances in cardiac
⁎ Corresponding author at: Department of Cardiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: + 31 20 566 9111; fax: + 31 20 696 2609. E-mail address: [email protected]
(B.J. Bouma). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
http://dx.doi.org/10.1016/j.ijcard.2014.04.072 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
surgery and medical care have resulted in a new population of adults with CHD [5–8]. This aging population is prone to develop a variety of sequelae including PAH. Recently, the clinical subclassiﬁcation of PAH-CHD has been updated and includes four phenotypes : Eisenmenger syndrome (group A), PAH associated with left-to-right shunts (group B), PAH with coincidental congenital heart disease (group C) and post-operative PAH (group D). Previous prevalence estimates of PAH among the general adult CHD population have mainly been extrapolated from tertiary hospital registries [10,11], or include patients with the entire spectrum of PAH , or only use diagnostic codes from databases to identify PAH patients . Furthermore, a large proportion of patients with CHD fail to receive adequate cardiac follow-up, either through misperception of ‘cure’
A.C.M.J. van Riel et al. / International Journal of Cardiology 174 (2014) 299–305
after undergoing repair of a cardiac defect or through possible denial of their chronic disease and coping difﬁculties with their limitations [14,15]. To optimize clinical and therapeutic care, it is important to have a clear and reliable estimate of PAH prevalence in CHD patients. Therefore, we aimed to assess the contemporary prevalence of PAH-CHD according to the new deﬁned clinical classiﬁcation , to identify those patient groups in which physicians should be aware of PAH-CHD and the associated therapeutic and clinical options. 2. Methods 2.1. Data source The Dutch Congenital Corvitia (CONCOR) population-based registry has been described previously and aims to facilitate research in adult patients with CHD . Due to national campaigns to detect and identify patients who were lost to follow-up and two permanently employed research nurses specialized in CHD, the registry contains a high amount of patients who are representative of the total CHD population . Clinical data, including events and diagnoses, are registered per patient by use of the European Pediatric Cardiac Code Short List coding scheme . 2.2. Study population and design In August 2011, the CONCOR registry contained records of 12,624 adults with CHD who were still alive, from 103 tertiary and secondary hospitals throughout the country. In this cross-sectional study, we ﬁrst identiﬁed all patients with an initial diagnosis of systemicto-pulmonary shunt. These patients were considered as the population at risk for developing PAH. The following diagnoses were included: atrial septal defect (ASD) type 2, sinus venosus ASD, ASD type 1, ventricular septal defect (VSD), complete atrioventricular septal defect (AVSD), patent ductus arteriosus (PDA), functionally univentricular heart (UVH), partial or total abnormal pulmonary venous drainage (PAPVD/TAPVD), double outlet
right ventricle, double inlet left ventricle, common arterial trunk, aortopulmonary window and combined shunts. Subsequently, we drew a random sample of the total population at risk. Stratiﬁcation was performed according to secondary or tertiary center, and the sample size of the subset was estimated using the assumption of a 10% prevalence of PAH , a margin of error of 1% and an alpha risk of error set at 5%. The sampling was designed to reﬂect the distribution that 60% of the total at-risk patients belonged to tertiary centers and 40% to secondary centers. 2.3. Prevalence The prevalence of PAH in at-risk patients was deﬁned by the number of adult patients born with systemic-to-pulmonary shunt who had PAH, divided by the total number of adult patients born with systemic-to-pulmonary shunt. To estimate the prevalence of PAH in all CHD patients, the number of PAH patients observed in the study was multiplied by the ratio of the number of CHD patients at risk of PAH (born with systemic-to-pulmonary shunt) to the number of patients in the random sample, and subsequently divided by all CHD patients registered in the CONCOR registry. To determine the prevalence of PAH among the different phenotypes of systemic-topulmonary shunts, patients from group B were grouped with patients without PAH and a large left-to-right shunt. Patients from group C were grouped with patients without PAH and a small defect, and patients from group D were grouped with post-operative patients without PAH. Only patients with Eisenmenger syndrome could not be grouped in this setting since there are no patients without PAH who have a similar phenotype. Subgroup calculation of prevalence was performed for different classes of severity. As there is large heterogeneity in classiﬁcation, separate lesions were redistributed according to a simpliﬁed version of the widely applied classiﬁcation of Warnes et al. . Finally, PAH prevalence was calculated per age category. 2.4. Data collection For all patients included in the random sample, we performed an extensive review of the medical records. Surgical and medical history, and latest recorded clinical status were obtained. Furthermore, echocardiographic reports were reviewed for cardiac function and
Fig. 1. Study population and design. The ﬁgure illustrates the derivation of the study population for the prevalence cohort. CHD—congenital heart disease; PAH—pulmonary arterial hypertension.
A.C.M.J. van Riel et al. / International Journal of Cardiology 174 (2014) 299–305 systolic pulmonary arterial pressure (sPAP) since invasive measurements were usually not available. Values of sPAP were obtained using right ventricular systolic pressure (RVSP) derived from continuous wave Doppler interrogation of tricuspid regurgitation, with addition of right atrial pressure estimated with measurement of inferior vena cava size and collapsibility . The presence of PAH was deﬁned as unlikely (sPAP ≤ 39 mmHg), or possible (sPAP ≥ 40 mmHg), with sPAP values measured at the last moment of physician contact . Patients without an available value of sPAP were classiﬁed as unlikely presence of PAH. Patients with a Fontan circulation, a documented pulmonary valve stenosis or right ventricle (RV) outﬂow tract obstruction were excluded from the analysis. Furthermore, patients with left sided cardiac valvular disease (i.e., moderate to severe aortic stenosis or regurgitation, and moderate to severe mitral stenosis or regurgitation) were also excluded since these conditions can lead to pulmonary venous hypertension. Finally, patients with various diseases that may interfere with the etiology of PAH were excluded, including HIV, severe chronic obstructive pulmonary disease, history of pulmonary embolism and chronic thrombo-embolic pulmonary hypertension. 2.5. Statistical analysis Data are summarized as number (%) for categorical variables, mean ± SD for continuous variables with normal distribution, and median (interquartile range, IQR) for continuous data with skewed distribution. Continuous variables between subgroups were analyzed using independent t test analysis, analysis of variance or Mann–Whitney U-test, where appropriate. Categorical data were evaluated using the chi-square statistic. All reported p values are two-sided, and values of p b 0.05 were considered signiﬁcant. Statistical analyses were performed using SPSS software (version 20.0).
(TIA) (n = 1, 2%) and endocarditis (n = 2, 4%), with a slightly higher number of patients with documented supraventricular tachycardia (SVT) (n = 10, 20%). Due to the complex nature of the Eisenmenger syndrome itself, all patients were classiﬁed as having a heart defect with great complexity. Current medication is listed in Table 2 and indicates that 73% of symptomatic patients (NYHA ≥ 2) received PAH speciﬁc therapy. In the remaining 27% (n = 12), there had been agreed upon a conservative treatment policy, mainly due to the presence of Down syndrome. 3.3. PAH associated with left-to-right shunt (Group B) In total, 15 patients were allocated to this clinical class group B, with a mean age of 48 ± 15 years. Median sPAP was 50 mmHg (IQR 44– 61 mmHg). Most of the patients were classiﬁed as functional class I while only 40% of patients did exhibit signs of heart failure (NYHA II and III). Furthermore, there was a high number of Down syndrome patients identiﬁed in this group (n = 7, 47%). Only two non-Down patients received PAH speciﬁc therapy (Table 2), two non-Down patients were awaiting closure of their defect, nine were on conservative treatment policy and two non-Down patients had a marginally elevated sPAP of 40 mmHg.
3.1. Patient population
3.4. PAH with coincidental congenital heart disease (Group C)
From all 12,624 registered CHD patients in the CONCOR registry who were alive in 2011, 5,487 (44%) were deﬁned as the population at risk. The random sample contained 1,868 subjects from 3 tertiary centers and 29 secondary centers spread across the country. In total, 54 patients were excluded, resulting in a study cohort of 1814 patients (Fig. 1), of whom 1,235 (68%) were from tertiary care and 579 (32%) from secondary care facilities. In total, 135 CHD patients with PAH were identiﬁed. Clinical characteristics of the 1,679 patients without PAH and the 135 PAH-CHD patients divided in clinical subgroups are shown in Table 1.
Only ﬁve patients could be categorized in this clinical class, with the highest mean age (61 ± 22) compared to the other PAH-CHD classes, and only one Down syndrome patient (20%). All patients were in NYHA functional class I, explaining the lack of PAH speciﬁc therapy in this group (Table 2). The severity of heart defects in this class was mild, with four simple VSDs and one simple ASD. All shunts were small, without a signiﬁcant left-to-right shunt that was considered causal to the elevated pressure found in the pulmonary circulation. Furthermore, the sPAP was only slightly elevated in this subclass with a median of 45 mmHg (IQR 42–50 mmHg).
3.2. Eisenmenger syndrome (Group A) 3.5. Post-operative PAH (Group D) This clinical subclass consisted of 51 patients, with the highest number of Down syndrome patients (n = 25, 51%) and the lowest mean age (42 ± 11 years) compared to the other PAH-CHD classes. The majority of patients (90%) were in NYHA class II–IV, and the median sPAP value was 83 mmHg (IQR 75–100 mmHg). Medical history documented a limited number of patients with stroke or transient ischemic attack
This clinical subclass includes the largest number of PAH-CHD patients (n = 64), with a mean age of 52 ± 18 years and 4 Down syndrome patients (7%). Although most patients were in NYHA class I (n = 43, 68%), one-third of patients had impaired functional capacity as expressed by NYHA class II or III (n = 20, 32%). However, only 9 symptomatic
Table 1 Clinical characteristics.
Age [years], mean ± SD Male sex, n (%) Down syndrome, n (%) NYHA functional class, n (%) I II III IV History of, n (%) Supraventricular tachycardia Heart defect severity⁎, n (% per group) Simple Moderate severity Great complexity Echocardiography sPAP [mmHg], median (IQR)
All patients (n = 1814)
No PAH (n = 1679)
Group A (n = 51)
Group B (n = 15)
Group C (n = 5)
Group D (n = 64)
40 ± 15 761 (42) 109 (6)
39 ± 14 709 (42) 72 (5)
42 ± 11 19 (37) 25 (51)
48 ± 15 6 (40) 7 (47)
61 ± 22 2 (40) 1 (20)
52 ± 18 25 (39) 4 (7)
b0.001 0.94 b0.001
1575 (87) 146 (8) 35 (2) 1 (0.1)
1513 (93) 105 (7) 6(0.4) 0
5 (10) 22 (44) 22 (44) 1 (2)
9 (60) 5 (33) 1 (7) 0
5 (100) 0 0 0
43 (68) 14 (22) 6 (10) 0
1115 (61) 542 (30) 157 (9)
1063 (63) 514 (31) 102 (6)
0 0 51 (100)
6 (40) 7 (47) 2 (13)
5 (100) 0 0
41 (64) 21 (33) 2 (3)
Values are presented as mean ± SD, median (IQR - interquartile range) or as counts (percentages). PAH - pulmonary arterial hypertension; BMI - body mass index; NYHA - new york heart association functional class; sPAP - systolic pulmonary arterial pressure. ⁎ Following the classiﬁcation of Warnes et al. (21)
A.C.M.J. van Riel et al. / International Journal of Cardiology 174 (2014) 299–305
Table 2 Current medication of 135 patients with PAH-CHD. Group A n = 51
Group B n = 15
Group C n=5
Group D n = 64
Diuretics Digitalis Calcium channel blockers Oral anticoagulant treatment
16 (31) 11 (22) 3 (6) 12 (24)
3 (20) 1 (7) 0 3 (20)
2 (40) 0 1 (20) 2 (40)
20 (32) 10 (16) 3 (5) 32 (51)
NYHA functional class ≥ 2 PAH speciﬁc therapy Prostanoids Phosphodiesterase type-5 inhibitors Endothelin receptor antagonists Combination therapy
n = 45 (90%) 33 (73) 0 2 27 4
n = 6 (40%) 2 (33) 0 0 2 0
n = 20 (31%) 9 (45) 1 2 4 2
Values are presented as counts with percentages. PAH—pulmonary arterial hypertension; CHD—congenital heart disease NYHA - new york heart association.
patients (45%) received PAH speciﬁc therapy (Table 2). Furthermore, a large amount of patients had documented SVT (n = 25, 40%). Severity of underlying heart defects was mild in about two-thirds of patients, and moderate to severe in the remaining 36%. Median pressure in the pulmonary circulation was 44 mmHg (IQR 41–53 mmHg). Age at closure was signiﬁcantly higher compared to patients who underwent closure without PAH development. Median age at closure was 24 years (IQR 5– 56 years) in PAH patients vs. 7 years (IQR 2–23 years) in patients without PAH development (p b 0.001).
3.6. Prevalence of PAH Of the 1,814 reviewed CHD patients alive in 2011, 135 had possible PAH (prevalence of 7.4%). A detailed description of the prevalence calculation of PAH-CHD is mentioned in the Methods section and shown in Table 3. To calculate the prevalence of PAH in the entire CHD population, we multiplied the number of PAH patients (n = 135) with the ratio between the sample size and total cohort of patients born with systemic-to-pulmonary shunt (5,487 / 1,814 = 3.0). The prevalence of PAH in the total CHD population could be estimated as follows: [(135 × 3.0) / 12,624] × 100 = 3.2%. Based on our data and recently published data suggesting a prevalence of CHD in the adult population of 3 000 per million adults , we can estimate a prevalence of PAHCHD in the whole general adult population of approximately 100 per million (Table 3).
Table 3 Prevalence of pulmonary arterial hypertension.
3.7. Prevalence per clinical class Table 4 represents the distribution of all 135 PAH-CHD patients according to each clinical subclassiﬁcation. Groups B, C and D were matched with non-PAH patients, to provide an estimate of the prevalence of PAH in each clinical subtype. As described in the Methods section, Eisenmenger patients could not be grouped in a similar way. As a result thereof, the prevalence of PAH in group A is 100%. Half of the patients with a large left-to-right shunt (group B) had PAH (50%). The number of patients with PAH in group C (PAH with coincidental CHD) was only 5 out of 465, resulting in a prevalence of 1%. The prevalence of PAH among all patients who received corrective cardiac surgery or intervention for their heart defect, 64 out of 1120 have residual or recurrent PAH, leading to a prevalence of 5.7%. There was no signiﬁcant difference in the development of PAH between patients who underwent percutaneous or surgical closure of their defect.
3.8. Prevalence per defect The presence of PAH per defect was calculated per severity of defect, results are presented in Table 5. In patients with mild defects, the prevalence of PAH was 5.9%. Moderate defects present the highest prevalence of PAH (11.1%), mainly driven by the high prevalence among AVSD patients (34.4%). The prevalence of PAH in patients with severe defects is lower than moderate defects (8.7%), which could be explained by the higher mortality rate in these patients and possibly by correction of the cardiac defect at a younger age in these severe conditions which could prevent PAH development. Fig. 2 displays the distribution of all PAH-CHD patients (n = 135) according to underlying cardiac defect. Patients with Eisenmenger syndrome had a predominance of post-tricuspid shunts, with AVSD being the most frequent underlying defect (n = 19, 37%). On the other hand, in patients with PAH after shunt closure pretricuspid shunts were more prevalent, especially ASD type 2 (simple ASD) in 29 patients (45%).
Registered CHD patients in CONCOR alive in 2011
Patients with systemic to pulmonary shunts
Stratiﬁed sample size
Patients with PAH in sample size
3.9. Prevalence per age category
PAH prevalence in CHD patients with systemic to pulmonary shunt
PAH prevalence in adult CHD patients
PAH prevalence in general adult population (per million inhabitants)
Fig. 3 illustrates the increasing prevalence of PAH in patients born with a systemic-to-pulmonary shunt related to age category. Where the prevalence of PAH in patients under 30 years of age is rather low (2.5%), this rapidly increases to about 10% in patients from 30 to 60 years old. Until the age of 70, the prevalence increases to 13.8%, and above 70 years even higher rates are found with a prevalence of 24.3% in patients from 70 to 79 years old and 35% in the oldest patients of our cohort.
PAH—pulmonary arterial hypertension; CHD—congenital heart disease.
A.C.M.J. van Riel et al. / International Journal of Cardiology 174 (2014) 299–305 Table 4 Prevalence of PAH per clinical subclassiﬁcation.
A. Eisenmenger syndrome B. Left to right shunts C. PAH with coincidental congenital heart disease D. Post-operative PAH
51 15 5 64
15 460 1056
51 30 465 1120
100 50 1.1 5.7
PAH—pulmonary arterial hypertension. Patients grouped per underlying defect, shunt size and shunt direction, alive in 2011.
4. Discussion To our knowledge, this is the ﬁrst study to report robust prevalence estimates of PAH in a nationwide CHD population following the updated clinical classiﬁcation. Prevalence of PAH in patients born with a systemic-to-pulmonary shunt is 7.4%. The estimated prevalence of PAH among all adult CHD patients is 3.2%. Derived prevalence of PAH in the total adult population is 100/million inhabitants.
4.1. Prevalence In contrast to previous studies [10–13], our source population consisted only of adults with CHD and the extensive review of medical records and echocardiography reports captures PAH diagnosis beyond the use of database encoding. Furthermore, our sample population was believed to be representative of the nationwide adult CHD population born with a systemic-to-pulmonary shunt because tertiary as well as secondary medical centers spread across the country were included,
Table 5 Pulmonary arterial hypertension prevalence per defect in patients with systemic-topulmonary shunt. PAH-CHD
n = 135
n = 1679
n = 1814
Mild Simple ASD⁎ Simple VSD⁎ PDA Total mild
36 30 1 67
401 575 111 1087
437 605 112 1155
8.2 5.0 0.9 5.9
Moderate Complex ASD† Complex VSD† ASD sinus venosus AVSD ostium primum AVSD PAPVC/TAPVC Total moderate
2 20 7 9 21 0 59
36 248 68 102 40 3 497
38 268 75 111 61 3 561
5.3 7.5 9.3 8.1 34.4 0 11.1
1 3 2 3 9
8 56 10 21 95
9 59 12 24 104
11.1 5.1 16.7 12.5 8.7
Severe Truncus arteriosus Ventricular/arterial inversion Functionally univentricular heart Double outlet RV or LV Total severe
ASD—atrial septal defect; VSD—ventricular septal defect; AVSD—atrioventricular septal defect. PAPVC—partial anomalous pulmonary venous drainage; TAPVC—total anomalous pulmonary venous drainage. RV—right ventricle; LV—left ventricle. ⁎ Simple ASD and VSD comprises atrial or ventricular septal defect without associated lesions. † Complex ASD and VSD comprises atrial or ventricular septal defect with associated lesions like partial or total abnormal pulmonary venous drainage, aortic coarctation, mitral disease, or straddling tricuspid or mitral valve .
and patients at home recruited by means of a public campaign. This is a signiﬁcant improvement compared to previous studies, in which patients attending specialized tertiary referral centers and those with Eisenmenger syndrome were overrepresented.
4.2. Clinical classiﬁcation In patients with Eisenmenger syndrome, the pulmonary-to-systemic shunt and reduction of systemic blood oxygenation on exercise explains the lower exercise capacity . Although speciﬁc PAH medical therapy has been proven beneﬁcial in several clinical trials and longitudinal cohort studies [25–27], not all symptomatic Eisenmenger syndrome and left-to-right shunt patients in our cohort were receiving advanced treatment. This is mainly explained by the high number of Down syndrome patients, in whom determination of exercise capacity is often limited due to their intellectual disability . Moreover, a conservative treatment approach is often considered in patients with Down syndrome, since treatment with PAH speciﬁc therapy has not been proven beneﬁcial in terms of quality of life and exercise capacity in these patients , and obtaining reimbursement is often challenging. Another explanation might be that these patients have often been living with their symptoms for many years. It is possible that they adapt to everyday activities with a lower intensity and often underestimate the extent to which their symptoms inﬂuence their activities, which can affect functional classiﬁcation and thereby treatment strategy [29,30]. Patients with PAH and coincidental CHD formed only 4% of the total PAH-CHD population of this study, and only 1% of all patients with these small shunts develop PAH (Table 4). In these cases, the inﬂuence of the congenital heart defect in the induction and progression of pulmonary vascular disease is unclear and therefore the diagnosis of idiopathic PAH with a concomitant congenital defect has been proposed. However, previous studies have shown that the survival of patients with PAH associated with small defects is far better when compared to idiopathic PAH patients [6,31]. Possible explanations include the favorable prognostic inﬂuence of the small defects, which may allow a pulmonaryto-systemic shunt in the advanced stages, limiting the progressive reduction of systemic output. Furthermore, the presence of only mild defects and only moderate elevation of sPAP, made the diagnosis idiopathic PAH highly unlikely in these patients. The majority of PAH-CHD patients were classiﬁed as having postoperative PAH. The possible reasons for the initiation and progression of PAH in these subjects include a delayed correction of the defect, especially if pulmonary vascular disease had already developed. In our study we endorse this hypothesis, as patients from our cohort were corrected at a relatively late age (median age 24 years). Previous reports have shown a worse prognosis for these patients with closed defects, compared to other PAH-CHD patients [6,32]. This could be explained by a lack of an available pulmonary-to-systemic shunt in the case of elevation of pulmonary pressures or impaired adaptation of the right ventricle to an increasing after-load. Whether this is also true for our cohort needs further elucidation in a prospective setting. Nonetheless, this clinical class represent the largest group of PAH patients in our study and a PAH prevalence of 5.7% after closure is a concerning amount. Especially since 11 out of 20 symptomatic patients (55%) did not receive PAH speciﬁc therapy (Table 2) and the previously described mortality risk, we would like to emphasize that the awareness of PAH in patients after shunt closure should be increased to guarantee optimal treatment and medical care and lifelong cardiac followup is recommended in these patients. Furthermore, future research should aim to provide more insight into which patients are at highest risk to develop post-operative PAH, to be able to provide tailored care to patients born with systemic-to-pulmonary shunts. Because not every patient has necessarily beneﬁt from closure of a defect in terms of mortality and morbidity, especially when the shunt is discovered late in life.
A.C.M.J. van Riel et al. / International Journal of Cardiology 174 (2014) 299–305
Fig. 2. Total number of PAH-CHD patients (n = 135) per type of systemic-to-pulmonary shunt and clinical classiﬁcation. PAH-CHD—pulmonary arterial hypertension associated with congenital heart disease; ASD—atrial septal defect; VSD—ventricular septal defect; AVSD—atrioventricular septal defect; PDA—patent ductus arteriosus; UVH—univentricular heart; DORV/LV—double outlet right ventricle/left ventricle. *Complex ASD and VSD comprises atrial or ventricular septal defect with associated lesions like; partial or total abnormal pulmonary venous drainage, aortic coarctation, mitral disease or straddling tricuspid or mitral valve. †Simple ASD and VSD comprises atrial or ventricular septal defect without associated lesions.
4.3. Study limitations The cross-sectional study design is an efﬁcient way to evaluate a large sample of patients, and to generate hypotheses regarding the patient population investigated. However, because exposure and outcome are assessed simultaneously, there is no evidence of a temporal relationship between the two. Furthermore, the use of the CONCOR registry can underestimate our data, since only patients
who developed PAH and survived until entry in the registry could be included in our analysis. As such, there was a potential selection bias in our study toward including individuals with more favorable survivorship. However, in this study, the bias will have affected all four clinical subgroups. Regarding the echocardiographic evaluation of sPAP, we would like to remark that the noninvasive evaluation of pulmonary pressures with transthoracic echocardiography is feasible and measurements are
Fig. 3. Prevalence of PAH per age category in patients with a systemic-to-pulmonary shunt. PAH—pulmonary arterial hypertension CHD - congenital heart disease.
A.C.M.J. van Riel et al. / International Journal of Cardiology 174 (2014) 299–305
widely available in nearly all CHD patients. However, its intrinsic and operator-dependent limitations make early PAH diagnosis and screening challenging . Previous studies have shown that trans-thoracic Doppler echocardiography compared to right heart catheterization is acceptable and thus allows for valid population studies [34,35]; therefore, it seems reasonable to consider sPAP ≥ 40 mmHg at rest as possible PAH [36–38]. 5. Conclusions This new approach using a nationwide CHD population reports a PAH prevalence of 3.2% in CHD patients, and 100 per million in the general adult population. Especially in patients after shunt closure and the elderly, physicians should be aware of PAH-CHD, to provide optimal therapeutic and clinical care. Acknowledgements This study was supported by an unrestricted research grant from Actelion Pharmaceuticals Ltd. The authors would like to thank Mrs. C.J.M. Engelfriet and Mrs. S. Mantels for their dedicated work regarding the continuous data collection for the CONCOR registry and Ms. E.C. Gertsen for her help in collecting clinical data regarding this study. The work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI is part of and funded by the Dutch Federation of University Medical Centers. References  Vis JC, Duffels MG, Mulder P, et al. Prolonged beneﬁcial effect of bosentan treatment and 4-year survival rates in adult patients with pulmonary arterial hypertension associated with congenital heart disease. Int J Cardiol Mar 20 2013;164(1):64–9.  Schuuring MJ, van Riel ACMJ, Vis JC, et al. High-sensitivity troponin T is associated with poor outcome in adults with pulmonary arterial hypertension due to congenital heart disease. Congenit Heart Dis 2013;8(6):520–6.  Duffels M, van Loon L, Berger R, et al. Pulmonary arterial hypertension associated with a congenital heart defect: advanced medium-term medical treatment stabilizes clinical condition. Congenit Heart Dis Aug 2007;2(4):242–9.  Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J Nov 2005;26(21):2325–33.  Mulder BJM. Changing demographics of pulmonary arterial hypertension in congenital heart disease. Eur Respir Rev Off J Eur Respir Soc Dec 1 2010;19(118):308–13.  Manes A, Palazzini M, Leci E, Bacchi Reggiani ML, Branzi A, Galiè N. Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. Eur Heart J 2014;35(11):716–24.  Mulder BJM. Epidemiology of adult congenital heart disease: demographic variations worldwide. Neth Heart J Mon J Neth Soc Cardiol Neth Heart Found Dec 2012;20(12):505–8.  Tutarel O, Kempny A, Alonso-Gonzalez R, et al. Congenital heart disease beyond the age of 60: emergence of a new population with high resource utilization, high morbidity, and high mortality. Eur Heart J 2014;35:725–32.  Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classiﬁcation of pulmonary hypertension. J Am Coll Cardiol Dec 24 2013;62(25 Suppl.):D34–41.  Rose ML, Strange G, King I, et al. Congenital heart disease-associated pulmonary arterial hypertension: preliminary results from a novel registry. Intern Med J Aug 2012;42(8):874–9.  Engelfriet PM, Duffels MGJ, Möller T, et al. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart Br Card Soc Jun 2007;93(6):682–7.  Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med May 1 2006;173(9):1023–30.  Lowe BS, Therrien J, Ionescu-Ittu R, Pilote L, Martucci G, Marelli AJ. Diagnosis of pulmonary hypertension in the congenital heart disease adult population impact on outcomes. J Am Coll Cardiol Jul 26 2011;58(5):538–46.
 Warnes CA. The adult with congenital heart disease: born to be bad? J Am Coll Cardiol Jul 5 2005;46(1):1–8.  Mackie AS, Ionescu-Ittu R, Therrien J, Pilote L, Abrahamowicz M, Marelli AJ. Children and adults with congenital heart disease lost to follow-up: who and when? Circulation Jul 28 2009;120(4):302–9.  Van der Velde ET, Vander VET, Vriend JWJ, et al. CONCOR, an initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: rationale, design, and ﬁrst results. Eur J Epidemiol 2005;20(6):549–57.  Vis JC, van der Velde ET, Schuuring MJ, et al. Wanted! 8000 heart patients: identiﬁcation of adult patients with a congenital heart defect lost to follow-up. Int J Cardiol Jun 2 2011;149(2):246–7.  Franklin RCG, Anderson RH, Daniëls O, et al. Report of the Coding Committee of the Association for European Paediatric Cardiology. Cardiol Young Dec 2002;12(6):611–8.  D'Alto M, Mahadevan VS. Pulmonary arterial hypertension associated with congenital heart disease. Eur Respir Rev Off J Eur Respir Soc Dec 1 2012;21(126):328–37.  Warnes CA, Liberthson R, Danielson GK, et al. Task force 1: the changing proﬁle of congenital heart disease in adult life. J Am Coll Cardiol Apr 2001;37(5):1170–5.  Rudski LG, Lai WW, Aﬁlalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr Jul 2010;23(7):685–713 [quiz 786–788].  Bossone E, D'Andrea A, D'Alto M, et al. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr Jan 2013;26(1):1–14.  Van der Bom T, Bouma BJ, Meijboom FJ, Zwinderman AH, Mulder BJM. The prevalence of adult congenital heart disease, results from a systematic review and evidence based calculation. Am Heart J Oct 2012;164(4):568–75.  Diller G-P, Dimopoulos K, Okonko D, et al. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation Aug 9 2005;112(6):828–35.  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 congenital heart disease with and without Down's syndrome. Am J Cardiol May 1 2009;103(9):1309–15.  Schuuring MJ, Vis JC, Duffels MG, Bouma BJ, Mulder BJ. Adult patients with pulmonary arterial hypertension due to congenital heart disease: a review on advanced medical treatment with bosentan. Ther Clin Risk Manag 2010;6:359–66.  Baumgartner H, Bonhoeffer P, De Groot NMS, et al. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J Dec 2010;31(23):2915–57.  Vis JC, Thoonsen H, Duffels MG, et al. Six-minute walk test in patients with Down syndrome: validity and reproducibility. Arch Phys Med Rehabil Aug 2009;90(8):1423–7.  Dimopoulos K, Giannakoulas G, Wort SJ, Gatzoulis MA. Pulmonary arterial hypertension in adults with congenital heart disease: distinct differences from other causes of pulmonary arterial hypertension and management implications. Curr Opin Cardiol Nov 2008;23(6):545–54.  Raphael C, Briscoe C, Davies J, et al. Limitations of the New York Heart Association functional classiﬁcation system and self-reported walking distances in chronic heart failure. Heart Br Card Soc Apr 2007;93(4):476–82.  Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation Jul 13 2010;122(2):156–63.  Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006. Heart Br Card Soc Feb 2009;95(4):312–7.  Howard LS, Grapsa J, Dawson D, et al. Echocardiographic assessment of pulmonary hypertension: standard operating procedure. Eur Respir Rev Off J Eur Respir Soc Sep 1 2012;21(125):239–48.  D'Alto M, Romeo E, Argiento P, et al. Accuracy and precision of echocardiography versus right heart catheterization for the assessment of pulmonary hypertension. Int J Cardiol 2013;168(4):4058–62.  Wang B, Feng Y, Jia L-Q, et al. Accuracy of Doppler echocardiography in the assessment of pulmonary arterial hypertension in patients with congenital heart disease. Eur Rev Med Pharmacol Sci Apr 2013;17(7):923–8.  Badesch DB, Champion HC, Sanchez MAG, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol Jun 30 2009;54(1 Suppl.): S55–66.  McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation Dec 4 2001;104(23):2797–802.  Rubin LJ, Badesch DB. Evaluation and management of the patient with pulmonary arterial hypertension. Ann Intern Med Aug 16 2005;143(4):282–92.