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Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure
IJCA-16456; No of Pages 5 International Journal of Cardiology xxx (2013) xxx–xxx
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Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure☆ Michele D'Alto ⁎,1, Emanuele Romeo, Paola Argiento, Anna Correra, Giuseppe Santoro, Gianpiero Gaio, Berardo Sarubbi, Raffaele Calabrò, Maria Giovanna Russo Department of Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy
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Article history: Received 3 March 2013 Received in revised form 8 May 2013 Accepted 20 June 2013 Available online xxxx Keywords: Pulmonary hypertension Hemodynamics Congenital heart diseases
a b s t r a c t Background: Pulmonary arterial hypertension (PAH) after shunt closure is associated with a poor prognosis. The aim of this study was to assess retrospectively the hemodynamics of patients developing PAH after shunt closure. Methods: Hemodynamic data obtained by right heart catheterization (RHC) performed at baseline and after shunt closure were analyzed. Results: Twenty-two patients, 13 with atrial septal defect (ASD), 6 with ventricular septal defect (VSD), 1 with patent ductus arteriosus, 1 with both ASD and VSD, and 1 with complete atrio-ventricular canal have been considered. The mean age at closure was 25.3 ± 20.1 years (range of 3 months to 56.7 years), and the mean age at PAH diagnosis was 37.0 ± 20.8 years (range of 5 to 61.2 years). The time delay between shunt closure and PAH diagnosis was 140.2 ± 100.2 months. At baseline RHC, hemodynamic data were as follows: pulmonary vascular resistance (PVR) of 8.6 ± 2.6 Wood units, PVR index (PVRi) of 10.1 ± 2.7 Wood units ∗ m2, mean pulmonary arterial pressure of 43.7 ± 9.7 mm Hg, PVR to systemic vascular resistance ratio (PVR/SVR) of 0.70 ± 0.23, and Qp/Qs of 1.6 ± 0.4. In particular, 18/22 (81%) had PVR ≥ 5 Wood units, 21/22 (95%) PVRi ≥ 6 Wood units ∗ m2, 21/22 (95%) PVR/SVR ≥ 0.33, and 11/22 (50%) Qp/Qs ≤ 1.5. During the follow-up, 5/22 (22%) patients died and one patient underwent successful double lung transplantation. Conclusions: High baseline values of PVR (≥5 Wood units), PVRi (≥6 Wood units ∗ m2) and PVR/SVR (≥0.33) are common findings in patients who develop PAH late after shunt closure. Large prospective clinical trials are needed to establish the safe limits for shunt closure. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The clinical classification of congenital heart diseases (CHD) associated with pulmonary arterial hypertension (PAH) includes a condition that may occur after surgical or percutaneous closure of a cardiac shunt [1]. In these cases, CHD has been corrected but PAH is either still present immediately after shunt closure or has recurred several months or years after the procedure in the absence of significant postoperative residual congenital lesions or defects that originate as a sequela to previous surgery. Patients who develop PAH after shunt closure have a poorer prognosis than patients with uncorrected PAH–CHD [2], which has raised concerns regarding correction of congenital heart defects in patients with overt PAH. ☆ No grant support or any potential conflicts of interest, including related consultancies, shareholdings and funding grants. ⁎ Corresponding author at: Via Tino di Camaino, 6, 80128 Naples, Italy. Tel.: + 39 0817062501. E-mail address: [email protected] (M. D'Alto). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
The recent grown-up congenital heart disease (GUCH) guidelines [3] suggest a Qp/Qs N 1.5 and a pulmonary vascular resistance (PVR) b5 Wood units as the hemodynamic upper limits for operability in patients with atrial septal defects (ASD) or ventricular septal defects (VSD), discouraging shunt closure in the presence of severe PAH or Eisenmenger syndrome. The aim of this retrospective study was to assess hemodynamics in a consecutive cohort of patients referred to a single tertiary center for pulmonary hypertension (PH) who developed PAH after shunt closure. 2. Methods 2.1. Patient selection All consecutive patients who referred to an Italian tertiary PH center (Monaldi Hospital, Second University of Naples, Italy) for PAH developed after surgical or percutaneous closure of a cardiac shunt were considered. Concomitant causes of PH, such as lung or liver disease, were excluded using mandatory chest X-ray, respiratory function tests, perfusion lung scan, high-resolution computed tomography scan and abdominal ultrasound, according to current guidelines [1]. No lower or upper age limits were set.
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Please cite this article as: D'Alto M, et al, Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.036
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M. D'Alto et al. / International Journal of Cardiology xxx (2013) xxx–xxx
Informed consent (from the patient or the parents or the legal guardian, as appropriate) was obtained prior to entering the study. The protocol was approved by the institutional ethics committee. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. 2.2. Study design This was an open-label, retrospective study. 2.3. Clinical history A complete clinical history was collected for each patient, including a detailed description of the underlying CHD, hemodynamic assessment by right heart catheterization (RHC) performed at baseline, type of correction, age at correction, prescribed therapy before and after shunt closure, presence of concomitant diseases, and the clinical course until referral for suspected PH.
Baseline and follow-up hemodynamic data are reported in Tables 1 and 2, respectively. Notably, at baseline evaluation, 18/22 patients (81%) had PVR ≥5 Wood units and 21/22 patients (95%) had PVR index (PVRi) ≥6 Wood units ∗ m2. In addition, 21/22 patients (95%) had a PVR to systemic vascular resistance (PVR/SVR) ratio ≥ 0.33, and 11/22 patients (50%) had a Qp/Qs ≤ 1.5. Fig. 1 displays changes in PVR from baseline to follow-up RHC. Table 3 shows the clinical follow-up data of the study population and patient outcome. The time from PAH diagnosis at follow-up RHC to the end of the observation period was 4.4 ± 2.1 years (range of 1.2 to 8.2 years). During follow-up, 5/22 patients (22%) died and one patient underwent successful double lung transplantation. 4. Discussion
2.4. Clinical evaluation Clinical evaluation included assessment of WHO functional class and measurement of systemic arterial pressure, systemic pulse oximetry (SpO2) and heart rate. Resting systemic arterial oxygen saturation was measured by non-invasive finger pulse oximetry after 5 min of absolute rest in sitting position, and the mean of three consecutive readings was recorded for analysis. Clinical findings such as pretibial edema, jugular venous pulse and hepatomegaly were observed. Exercise capacity was evaluated with a non-encouraged 6-minute walk test [5,6]. The 6-minutewalk distance was calculated as the longest distance covered on two consecutive tests performed after 60–90 min. Heart rate and SpO2 were recorded at rest and after exercise. The Borg dyspnea index was obtained immediately after completion of the test. The 6-minute walk test was performed in a 25-m-long corridor under the same environmental conditions and at approximately the same time of the day (±2 h). 2.5. Right heart catheterization Hemodynamic assessment for suspected PH was performed by follow-up RHC according to current guidelines [1]. Right atrial, pulmonary artery, and pulmonary capillary wedge pressures as well as systemic pressure were recorded at the end of a quiet respiratory cycle. SpO2 in the superior vena cava, inferior vena cava, pulmonary artery and femoral artery was measured in triplicate. Pulmonary venous saturation was measured in patients with ASD or assumed as 96% in the remaining cases, according to medical literature on CHD–PAH [7]. Pulmonary and systemic blood flows were obtained with the Fick principle using table-derived oxygen consumption values and calculated oxygen content at the corresponding sites [8] in order to exclude the presence of residual shunts. 2.6. Exclusion criteria Patients who did not undergo preoperative hemodynamic assessment by RHC or with significant postoperative residual congenital lesions or defects developing as a sequela to previous surgery were excluded. 2.7. Statistical analysis Variables are presented as mean ± SD. Changes from baseline to 6-month follow-up were evaluated using paired Student's t test for continuous and non-continuous variables. A p value of b0.05 was considered statistically significant. All reported p values are two-tailed. Statistical analyses were performed using a commercially available SPSS software package (v. 14.0 2008; SPSS Inc., Chicago, Illinois).
3. Results Thirty consecutive patients (20 female) who developed PAH after shunt closure were evaluated. Eight out of 30 were excluded because of the lack of preoperative hemodynamic assessment (n = 6) and the presence of significant sequelae (n = 2). Of the remaining 22 patients (17 female), 13 had ASD, 6 had VSD, 1 had patent ductus arteriosus, 1 had both ASD and VSD, and 1 had complete atrio-ventricular canal (AVC). One out of 22 patients (4.5%) had Down's syndrome (the patient with AVC). No patient showed right heart failure or signs/symptoms related to PAH at 12 months after shunt closure. The mean age at closure was 25.3 ± 20.1 years (range of 3 months to 56.7 years), and the mean age at PAH diagnosis was 37.0 ± 20.8 years (range of 5 to 61.2 years). The time delay between shunt closure and PAH diagnosis at follow-up RHC was 140.2 ± 100.2 months (range of 40 to 358 months).
Our study results show that baseline PVR ≥ 5 Wood units, PVRi ≥ 6 Wood units ∗ m2 and PVR/SVR ≥ 0.33are common findings in patients who develop PAH late after shunt closure. According to the recent GUCH guidelines [3], patients with ASD having significant left-to-right shunting (Qp/Qs N 1.5 or signs of right ventricular volume overload) and PVR b 5 Wood units should undergo ASD closure regardless of symptoms. Similarly, patients with VSD are ideal candidates for closure if Qp/Qs is N1.5 and PVR is normal (b 5 Wood units). More recently, on the basis of current knowledge, Beghetti et al. [9] suggested a PVR b 6 Wood units together with a PVR/SVR ratio ≥0.3 following 12 months of PAH-specific therapy as the hemodynamic upper limit for operability. Consistent with the literature, in the present study patients who developed PAH after defect closure were likely to have PVR ≥5 Wood units at baseline evaluation (81% in our retrospective series). This PVR threshold may reflect a reliable hemodynamic marker of pulmonary vascular disease due to increased shear stress and circumferential stretch with subsequent endothelial dysfunction and vascular remodeling. Nevertheless, pulmonary vascular involvement as well as PVR and PVR/SVR values form a continuous spectrum of variation, which makes difficult to establish unquestionable limits that mark a point of no return. Notably, although a Qp/Qs N 1.5 is considered reassuring for shunt treatment, in our series 10/22 (45%) patients had Qp/Qs N 1.5 and 2/22 (9%) had Qp/Qs N 2 at baseline. It remains a clinical conundrum why patients with quite favorable hemodynamics (i.e., Qp/Qs N 1.5 and PVR b 5 Wood units as in our patients 3 and 8) develop PAH after shunt closure. It seems likely that a genetic predisposition or a subtle endothelial dysfunction may result in overt pulmonary vascular disease also in those patients who represent the best of the hemodynamic spectrum. A Qp/Qs N 2 may therefore be considered more appropriate to identify patients at low risk of developing PAH after shunt closure. Since that mean pulmonary arterial pressure (mPAP) depends on pulmonary flow (Q), capillary wedge pressure (PCWP) and vascular resistance [mPAP = PCWP + (PVR ∗ Q)], it is not surprising that mPAP before shunt closure is a poor predictor of pulmonary vascular disease. Elevated mPAP values may result from high flow conditions, typical of younger age, or high Qp/Qs. On the contrary, from a pathophysiological point of view, the increase in PVR (or PVRi) and PVRi/SVRi ratio is more likely related to significant pulmonary vascular involvement. In clinical practice, if PVR is above the recommended limits for surgical correction (N5 or 6 Wood units), a careful evaluation of pulmonary vascular reactivity should be performed to achieve the lowest PVR. In our retrospective series, only few patients (8/22) underwent acute vasoreactivity test. Because of the paucity of data and the different tests available (hyperoxia test using 100% FiO2, inhaled nitric oxide at 10 to 20 ppm, epoprostenol), this issue was not taken into consideration. Remarkably, no patient of our series showed right heart failure or signs/symptoms related to PAH at 12 months after shunt closure. In addition, the mean time delay between shunt closure and PAH diagnosis was longer than 10 years (140.2 ± 100.2 months). This suggests that
Please cite this article as: D'Alto M, et al, Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.036
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Table 1 Baseline hemodynamics of the study patients. Patient
CHD
Age (years)
Qp (l/min/m2)
Qp/ Qs
RAP (mm Hg)
PVR (WU)
PVRi (WU ∗ *m2)
PVR/ SVR
mPAP (mm Hg)
PCWP (mm Hg)
PaO2 (%)
SpO2 (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean SD
VSD ASD VSD VSD + ASD ASD ASD ASD AVC ASD ASD PDA ASD VSD ASD VSD ASD ASD ASD VSD VSD ASD ASD
5.4 32.1 7.1 3.3 55.3 28.3 43.9 7.0 56.4 12.3 8.9 56.7 4.0 42.2 0.25 52.0 26.0 32.1 6.9 4.9 29.0 42.9 25.3 20.1
3.2 2.6 3.5 5.3 3.2 3.7 3.2 2.6 3.6 5.3 3.8 2.9 3.8 3.4 3.5 3.6 4.2 3.6 3.8 3.2 3.5 2.9 3.6 0.7
1.5 1.1 2.1 1.3 1.3 1.7 1.3 3.0 1.6 1.6 1.1 1.9 1.3 1.9 1.3 1.6 2.1 1.4 1.2 1.8 1.3 1.9 1.6 0.4
9 12 10 7 8 5 8 7 5 10 9 6 11 6 14 5 6 5 8 12 11 7 8.2 2.6
4.3 8.0 4.1 11.5 4.8 5.6 5.3 4.7 5.4 12.0 11.8 7.9 11.3 6.0 15.0 5.8 13.8 6.7 11.8 11.3 15.0 7.7 8.6 3.7
5.3 12.3 6.0 7.2 8.4 8.9 8.4 8.1 10.3 6.8 11.8 13.1 11.3 9.1 15.4 10.0 9.5 10.3 11.8 10.9 15.4 12.4 10.1 2.7
0.38 0.44 0.60 0.80 0.30 0.73 0.35 0.92 0.54 0.79 0.83 0.69 0.88 0.63 1.20 0.52 1.10 0.60 0.79 0.95 0.76 0.71 0.70 0.23
25 44 29 44 35 41 35 32 42 45 53 44 53 42 64 42 48 42 53 43 64 42 43.7 9.7
8 12 8 6 8 8 8 11 5 9 8 6 10 11 10 6 8 5 8 8 10 6 8.1 2.0
73 68 75 74 78 85 78 62 77 76 77 72 70 88 75 77 63 77 77 73 70 72 74.4 5.9
95 92 98 91 90 96 92 98 94 93 89 90 92 94 92 94 97 92 91 93 89 96 93.1 2.7
ASD, atrial septal defect; CHD, congenital heart disease; mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; PVRi, PVR index; Qp/Qs, pulmonary to systemic flow ratio; RAP, right atrial pressure; SpO2, systemic pulse oximetry; PaO2, pulmonary arterial O2 saturation; SVR, systemic vascular resistance; VSD, ventricular septal defect; WU, Wood units.
PAH may develop or become clinically manifest many years after shunt repair. There is currently very limited experience and no long-term data available in patients with borderline hemodynamics undergoing shunt closure to raise concerns about defining a procedure as successful after a short follow-up (months or a few years). Indeed, patients may deteriorate years after an initial short-term improvement [10]. Timely correction of the underlying congenital heart defect (i.e., early in childhood) can actually prevent the development of PAH–CHD. However, a certain proportion of patients with left-to-right shunts are not
recognized until later in life when changes in pulmonary vasculature and PVR have already occurred. Currently, there are no established markers of reversibility in this gray zone, although a number of candidates have been proposed. To date, the most promising marker seems to be the number of circulating endothelial cells. This is a non-invasive marker of vascular damage and remodeling, which has been shown to be significantly raised in CHD patients with irreversible PAH postsurgery [11]. Further studies are required to confirm whether this is an appropriate marker. There are no evidence-based algorithms to guide
Table 2 Hemodynamics of the study patients after shunt closure. Patient
CHD
Age (years)
Time delay (months)
Qp (l/min/m2)
RAP (mm Hg)
PVR (WU)
PVRi (WU* ∗ m2)
mPAP (mm Hg)
PCWP (mm Hg)
PaO2 (%)
SpO2 (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean SD
VSD ASD VSD VSD + ASD ASD ASD ASD AVC ASD ASD PDA ASD VSD ASD VSD ASD ASD ASD VSD VSD ASD ASD
9.2 37.7 22.4 25.4 60.2 49.2 52.1 28.2 60.1 31.2 12.2 61.2 8.1 72.0 5.0 61.0 49.2 37.7 22.4 8.2 49.2 52.1 37.0 20.8
46 67 184 265 59 251 98 254 44 227 40 54 49 358 57 108 278 67 186 40 242 110 140.2 100.3
3.8 2.5 3.1 3.9 3.2 3.4 3.0 1.9 1.7 2.5 1.9 2.7 1.8 2.3 2.8 2.8 4.1 2.5 2.2 3.2 2.3 2.5 2.7 0.7
4 5 7 8 14 5 15 28 15 28 20 9 15 3 5 12 5 5 7 4 5 15 10.6 7.4
7.4 4.6 13.2 14.7 4.4 7.8 3.5 22.9 8.9 18.4 38.3 2.9 15.0 4.9 20.4 4.8 5.8 4.6 18.6 8.8 10.5 5.0 11.2 8.6
10.8 7.1 19.4 23.6 7.8 12.4 5.7 38.9 17.1 26.9 31.3 4.8 26.7 7.3 19.6 8.2 9.3 7.1 27.3 12.8 17.0 8.0 15.9 9.7
46 25 67 100 35 50 30 85 38 80 68 26 60 26 62 34 50 25 67 46 50 30 50.0 21.4
5 7 7 8 10 8 13 11 9 14 8 13 12 9 7 11 12 7 7 5 11 10 9.3 2.6
80 73 75 85 82 82 63 60 65 65 68 72 60 69 62 80 82 73 75 80 82 63 72.5 8.3
97 96 98 97 96 96 95 89 88 96 86 95 85 91 94 93 97 93 97 96 87 98 93.6 4.1
ASD, atrial septal defect; CHD, congenital heart disease; mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; PVRi, PVR index; Qp/Qs, pulmonary to systemic flow ratio; RAP, right atrial pressure; PaO2, pulmonary arterial O2 saturation; SpO2, systemic pulse oximetry; SVR, systemic vascular resistance; VSD, ventricular septal defect; WU, Wood units.
Please cite this article as: D'Alto M, et al, Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.036
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M. D'Alto et al. / International Journal of Cardiology xxx (2013) xxx–xxx
Fig. 1. Pulmonary vascular resistance (PVR) expresses in Wood units (WU) at baseline and at follow-up.
assessment for operability in these patients, and decisions should be based on careful evaluation of the individual patient. There are several arguments both in favor and against repair of congenital heart defects in patients with still net left-to-right shunt and moderately high PVR [12]. On one hand, in these patients shunt closure may abort right-to-left shunting, reduce cerebrovascular events, prevent cyanosis and its consequences, and protect the pulmonary circulation. On the other hand, leaving these patients untreated may prevent progression of Eisenmenger physiology to idiopathic PAH (having a worse long-term outcome) while avoiding high-risk surgery. In addition, no long-term data are available in this setting. In the last years, there has been increasing interest in the potential for use of PAH-specific therapies in the so-called “treat-and-repair”
Table 3 Clinical follow-up data of the study patients after PAH diagnosis. Patient
CHD
WHO FC at last observation
Medications
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean SD
VSD ASD VSD VSD + ASD ASD ASD ASD AVC ASD ASD PDA ASD VSD ASD VSD ASD ASD ASD VSD VSD ASD ASD
2 2 3 1 2 2 3 – – – 2 2 – 2 3 2 3 – 3 1 3 3 2.3 0.7
bos bos amb bos sil bos bos bos bos bos sil bos bos sil bos sil bos bos amb bos bos bos
– – sil sil – sil sil sil sil sil – – sil – sil – sil – sil – sil sil
– – – epo – – – – – tre – – epo – – – – – – – – –
war war war war war war war – war war – war war war – war – war war war war war
Time from PAH diagnosis (years)
Outcome
3.1 3.2 5.4 8.2 4.5 6.1 6.5 7.2 6.2 2.6 1.4 7.4 1.8 6.8 3.5 3 2.3 3.6 5.4 1.2 4.2 5.6 4.4 2.1
A A A LTx A A A Dead Dead Dead A A Dead A A A A Dead A A A A
A, alive; ASD, atrial septal defect; amb, ambrisentan; bos, bosentan; CHD, congenital heart disease; epo, epoprostenol; LTx, lung transplantation; sil, sildenafil; VSD, ventricular septal defect; war, warfarin; WHO FC, World Health Organization functional class.
strategy aimed at reducing PVR, thus improving operability of patients with PAH–CHD. However, available data on closure of intra- or extra cardiac shunts in the presence of severe PAH, with or without the use of targeted PAH therapies (“treat-and-repair” approach), are scarce and still limited to case reports [13–17] or case series [10,18]. Initial results appear promising, but in most cases follow-up was relatively short, and the long-term adaptation of the right ventricle after correction of the congenital heart defect remains unknown. Consistent with other studies [2,19], the clinical course of PAH in previously repaired defects was not benign in our series, showing a high mortality rate (22% death and one lung transplantation over 4.4 years of follow-up). This observation raises concerns about repairing CHD in patients with overt PH or “borderline” hemodynamics, because their outcome may be worse with corrected than with uncorrected shunt, mainly as a consequence of the loss of the defect, which represents a “relief valve” for the right heart chambers. In conclusion, high baseline values of PVR (≥ 5 Wood units), PVRi (≥6 Wood units ∗ m2) and PVR/SVR (≥0.33) are common findings in patients who develop PAH after shunt closure. A Qp/Qs N 2 may be considered reassuring before shunt closure. PAH may develop or become clinically manifest years after shunt repair. The clinical course of PAH in previously repaired defects was not benign, showing a high mortality rate. However, owing to the limited amount of data, large prospective clinical trials are needed to establish the safe limits for shunt closure.
4.1. Limitations of the study This is a retrospective, single center study. The main limitation of this study is that it included only patients referred for PAH development, without allowing evaluation of patients with similar hemodynamics who had a favorable outcome. This is a strong bias against treatment of patients with “borderline” hemodynamics. However, the aims of this retrospective study were to assess baseline hemodynamics of patients who developed PAH after shunt closure and not to establish the safe limits for surgical or percutaneous correction. Another important study limitation is that the time delay between shunt closure and PAH diagnosis at follow-up RHC does not necessarily indicate the time for developing PAH, as, theoretically, each patient should manifest PAH immediately after shunt closure. Finally, a not negligible proportion of patients (8/30, 27%) developing PAH after shunt closure did not undergo baseline hemodynamic assessment.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure☆ Michele D'Alto ⁎,1, Emanuele Romeo, Paola Argiento, Anna Correra, Giuseppe Santoro, Gianpiero Gaio, Berardo Sarubbi, Raffaele Calabrò, Maria Giovanna Russo Department of Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy
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Article history: Received 3 March 2013 Received in revised form 8 May 2013 Accepted 20 June 2013 Available online xxxx Keywords: Pulmonary hypertension Hemodynamics Congenital heart diseases
a b s t r a c t Background: Pulmonary arterial hypertension (PAH) after shunt closure is associated with a poor prognosis. The aim of this study was to assess retrospectively the hemodynamics of patients developing PAH after shunt closure. Methods: Hemodynamic data obtained by right heart catheterization (RHC) performed at baseline and after shunt closure were analyzed. Results: Twenty-two patients, 13 with atrial septal defect (ASD), 6 with ventricular septal defect (VSD), 1 with patent ductus arteriosus, 1 with both ASD and VSD, and 1 with complete atrio-ventricular canal have been considered. The mean age at closure was 25.3 ± 20.1 years (range of 3 months to 56.7 years), and the mean age at PAH diagnosis was 37.0 ± 20.8 years (range of 5 to 61.2 years). The time delay between shunt closure and PAH diagnosis was 140.2 ± 100.2 months. At baseline RHC, hemodynamic data were as follows: pulmonary vascular resistance (PVR) of 8.6 ± 2.6 Wood units, PVR index (PVRi) of 10.1 ± 2.7 Wood units ∗ m2, mean pulmonary arterial pressure of 43.7 ± 9.7 mm Hg, PVR to systemic vascular resistance ratio (PVR/SVR) of 0.70 ± 0.23, and Qp/Qs of 1.6 ± 0.4. In particular, 18/22 (81%) had PVR ≥ 5 Wood units, 21/22 (95%) PVRi ≥ 6 Wood units ∗ m2, 21/22 (95%) PVR/SVR ≥ 0.33, and 11/22 (50%) Qp/Qs ≤ 1.5. During the follow-up, 5/22 (22%) patients died and one patient underwent successful double lung transplantation. Conclusions: High baseline values of PVR (≥5 Wood units), PVRi (≥6 Wood units ∗ m2) and PVR/SVR (≥0.33) are common findings in patients who develop PAH late after shunt closure. Large prospective clinical trials are needed to establish the safe limits for shunt closure. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The clinical classification of congenital heart diseases (CHD) associated with pulmonary arterial hypertension (PAH) includes a condition that may occur after surgical or percutaneous closure of a cardiac shunt [1]. In these cases, CHD has been corrected but PAH is either still present immediately after shunt closure or has recurred several months or years after the procedure in the absence of significant postoperative residual congenital lesions or defects that originate as a sequela to previous surgery. Patients who develop PAH after shunt closure have a poorer prognosis than patients with uncorrected PAH–CHD [2], which has raised concerns regarding correction of congenital heart defects in patients with overt PAH. ☆ No grant support or any potential conflicts of interest, including related consultancies, shareholdings and funding grants. ⁎ Corresponding author at: Via Tino di Camaino, 6, 80128 Naples, Italy. Tel.: + 39 0817062501. E-mail address: [email protected] (M. D'Alto). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
The recent grown-up congenital heart disease (GUCH) guidelines [3] suggest a Qp/Qs N 1.5 and a pulmonary vascular resistance (PVR) b5 Wood units as the hemodynamic upper limits for operability in patients with atrial septal defects (ASD) or ventricular septal defects (VSD), discouraging shunt closure in the presence of severe PAH or Eisenmenger syndrome. The aim of this retrospective study was to assess hemodynamics in a consecutive cohort of patients referred to a single tertiary center for pulmonary hypertension (PH) who developed PAH after shunt closure. 2. Methods 2.1. Patient selection All consecutive patients who referred to an Italian tertiary PH center (Monaldi Hospital, Second University of Naples, Italy) for PAH developed after surgical or percutaneous closure of a cardiac shunt were considered. Concomitant causes of PH, such as lung or liver disease, were excluded using mandatory chest X-ray, respiratory function tests, perfusion lung scan, high-resolution computed tomography scan and abdominal ultrasound, according to current guidelines [1]. No lower or upper age limits were set.
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Please cite this article as: D'Alto M, et al, Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.036
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Informed consent (from the patient or the parents or the legal guardian, as appropriate) was obtained prior to entering the study. The protocol was approved by the institutional ethics committee. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. 2.2. Study design This was an open-label, retrospective study. 2.3. Clinical history A complete clinical history was collected for each patient, including a detailed description of the underlying CHD, hemodynamic assessment by right heart catheterization (RHC) performed at baseline, type of correction, age at correction, prescribed therapy before and after shunt closure, presence of concomitant diseases, and the clinical course until referral for suspected PH.
Baseline and follow-up hemodynamic data are reported in Tables 1 and 2, respectively. Notably, at baseline evaluation, 18/22 patients (81%) had PVR ≥5 Wood units and 21/22 patients (95%) had PVR index (PVRi) ≥6 Wood units ∗ m2. In addition, 21/22 patients (95%) had a PVR to systemic vascular resistance (PVR/SVR) ratio ≥ 0.33, and 11/22 patients (50%) had a Qp/Qs ≤ 1.5. Fig. 1 displays changes in PVR from baseline to follow-up RHC. Table 3 shows the clinical follow-up data of the study population and patient outcome. The time from PAH diagnosis at follow-up RHC to the end of the observation period was 4.4 ± 2.1 years (range of 1.2 to 8.2 years). During follow-up, 5/22 patients (22%) died and one patient underwent successful double lung transplantation. 4. Discussion
2.4. Clinical evaluation Clinical evaluation included assessment of WHO functional class and measurement of systemic arterial pressure, systemic pulse oximetry (SpO2) and heart rate. Resting systemic arterial oxygen saturation was measured by non-invasive finger pulse oximetry after 5 min of absolute rest in sitting position, and the mean of three consecutive readings was recorded for analysis. Clinical findings such as pretibial edema, jugular venous pulse and hepatomegaly were observed. Exercise capacity was evaluated with a non-encouraged 6-minute walk test [5,6]. The 6-minutewalk distance was calculated as the longest distance covered on two consecutive tests performed after 60–90 min. Heart rate and SpO2 were recorded at rest and after exercise. The Borg dyspnea index was obtained immediately after completion of the test. The 6-minute walk test was performed in a 25-m-long corridor under the same environmental conditions and at approximately the same time of the day (±2 h). 2.5. Right heart catheterization Hemodynamic assessment for suspected PH was performed by follow-up RHC according to current guidelines [1]. Right atrial, pulmonary artery, and pulmonary capillary wedge pressures as well as systemic pressure were recorded at the end of a quiet respiratory cycle. SpO2 in the superior vena cava, inferior vena cava, pulmonary artery and femoral artery was measured in triplicate. Pulmonary venous saturation was measured in patients with ASD or assumed as 96% in the remaining cases, according to medical literature on CHD–PAH [7]. Pulmonary and systemic blood flows were obtained with the Fick principle using table-derived oxygen consumption values and calculated oxygen content at the corresponding sites [8] in order to exclude the presence of residual shunts. 2.6. Exclusion criteria Patients who did not undergo preoperative hemodynamic assessment by RHC or with significant postoperative residual congenital lesions or defects developing as a sequela to previous surgery were excluded. 2.7. Statistical analysis Variables are presented as mean ± SD. Changes from baseline to 6-month follow-up were evaluated using paired Student's t test for continuous and non-continuous variables. A p value of b0.05 was considered statistically significant. All reported p values are two-tailed. Statistical analyses were performed using a commercially available SPSS software package (v. 14.0 2008; SPSS Inc., Chicago, Illinois).
3. Results Thirty consecutive patients (20 female) who developed PAH after shunt closure were evaluated. Eight out of 30 were excluded because of the lack of preoperative hemodynamic assessment (n = 6) and the presence of significant sequelae (n = 2). Of the remaining 22 patients (17 female), 13 had ASD, 6 had VSD, 1 had patent ductus arteriosus, 1 had both ASD and VSD, and 1 had complete atrio-ventricular canal (AVC). One out of 22 patients (4.5%) had Down's syndrome (the patient with AVC). No patient showed right heart failure or signs/symptoms related to PAH at 12 months after shunt closure. The mean age at closure was 25.3 ± 20.1 years (range of 3 months to 56.7 years), and the mean age at PAH diagnosis was 37.0 ± 20.8 years (range of 5 to 61.2 years). The time delay between shunt closure and PAH diagnosis at follow-up RHC was 140.2 ± 100.2 months (range of 40 to 358 months).
Our study results show that baseline PVR ≥ 5 Wood units, PVRi ≥ 6 Wood units ∗ m2 and PVR/SVR ≥ 0.33are common findings in patients who develop PAH late after shunt closure. According to the recent GUCH guidelines [3], patients with ASD having significant left-to-right shunting (Qp/Qs N 1.5 or signs of right ventricular volume overload) and PVR b 5 Wood units should undergo ASD closure regardless of symptoms. Similarly, patients with VSD are ideal candidates for closure if Qp/Qs is N1.5 and PVR is normal (b 5 Wood units). More recently, on the basis of current knowledge, Beghetti et al. [9] suggested a PVR b 6 Wood units together with a PVR/SVR ratio ≥0.3 following 12 months of PAH-specific therapy as the hemodynamic upper limit for operability. Consistent with the literature, in the present study patients who developed PAH after defect closure were likely to have PVR ≥5 Wood units at baseline evaluation (81% in our retrospective series). This PVR threshold may reflect a reliable hemodynamic marker of pulmonary vascular disease due to increased shear stress and circumferential stretch with subsequent endothelial dysfunction and vascular remodeling. Nevertheless, pulmonary vascular involvement as well as PVR and PVR/SVR values form a continuous spectrum of variation, which makes difficult to establish unquestionable limits that mark a point of no return. Notably, although a Qp/Qs N 1.5 is considered reassuring for shunt treatment, in our series 10/22 (45%) patients had Qp/Qs N 1.5 and 2/22 (9%) had Qp/Qs N 2 at baseline. It remains a clinical conundrum why patients with quite favorable hemodynamics (i.e., Qp/Qs N 1.5 and PVR b 5 Wood units as in our patients 3 and 8) develop PAH after shunt closure. It seems likely that a genetic predisposition or a subtle endothelial dysfunction may result in overt pulmonary vascular disease also in those patients who represent the best of the hemodynamic spectrum. A Qp/Qs N 2 may therefore be considered more appropriate to identify patients at low risk of developing PAH after shunt closure. Since that mean pulmonary arterial pressure (mPAP) depends on pulmonary flow (Q), capillary wedge pressure (PCWP) and vascular resistance [mPAP = PCWP + (PVR ∗ Q)], it is not surprising that mPAP before shunt closure is a poor predictor of pulmonary vascular disease. Elevated mPAP values may result from high flow conditions, typical of younger age, or high Qp/Qs. On the contrary, from a pathophysiological point of view, the increase in PVR (or PVRi) and PVRi/SVRi ratio is more likely related to significant pulmonary vascular involvement. In clinical practice, if PVR is above the recommended limits for surgical correction (N5 or 6 Wood units), a careful evaluation of pulmonary vascular reactivity should be performed to achieve the lowest PVR. In our retrospective series, only few patients (8/22) underwent acute vasoreactivity test. Because of the paucity of data and the different tests available (hyperoxia test using 100% FiO2, inhaled nitric oxide at 10 to 20 ppm, epoprostenol), this issue was not taken into consideration. Remarkably, no patient of our series showed right heart failure or signs/symptoms related to PAH at 12 months after shunt closure. In addition, the mean time delay between shunt closure and PAH diagnosis was longer than 10 years (140.2 ± 100.2 months). This suggests that
Please cite this article as: D'Alto M, et al, Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.036
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Table 1 Baseline hemodynamics of the study patients. Patient
CHD
Age (years)
Qp (l/min/m2)
Qp/ Qs
RAP (mm Hg)
PVR (WU)
PVRi (WU ∗ *m2)
PVR/ SVR
mPAP (mm Hg)
PCWP (mm Hg)
PaO2 (%)
SpO2 (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean SD
VSD ASD VSD VSD + ASD ASD ASD ASD AVC ASD ASD PDA ASD VSD ASD VSD ASD ASD ASD VSD VSD ASD ASD
5.4 32.1 7.1 3.3 55.3 28.3 43.9 7.0 56.4 12.3 8.9 56.7 4.0 42.2 0.25 52.0 26.0 32.1 6.9 4.9 29.0 42.9 25.3 20.1
3.2 2.6 3.5 5.3 3.2 3.7 3.2 2.6 3.6 5.3 3.8 2.9 3.8 3.4 3.5 3.6 4.2 3.6 3.8 3.2 3.5 2.9 3.6 0.7
1.5 1.1 2.1 1.3 1.3 1.7 1.3 3.0 1.6 1.6 1.1 1.9 1.3 1.9 1.3 1.6 2.1 1.4 1.2 1.8 1.3 1.9 1.6 0.4
9 12 10 7 8 5 8 7 5 10 9 6 11 6 14 5 6 5 8 12 11 7 8.2 2.6
4.3 8.0 4.1 11.5 4.8 5.6 5.3 4.7 5.4 12.0 11.8 7.9 11.3 6.0 15.0 5.8 13.8 6.7 11.8 11.3 15.0 7.7 8.6 3.7
5.3 12.3 6.0 7.2 8.4 8.9 8.4 8.1 10.3 6.8 11.8 13.1 11.3 9.1 15.4 10.0 9.5 10.3 11.8 10.9 15.4 12.4 10.1 2.7
0.38 0.44 0.60 0.80 0.30 0.73 0.35 0.92 0.54 0.79 0.83 0.69 0.88 0.63 1.20 0.52 1.10 0.60 0.79 0.95 0.76 0.71 0.70 0.23
25 44 29 44 35 41 35 32 42 45 53 44 53 42 64 42 48 42 53 43 64 42 43.7 9.7
8 12 8 6 8 8 8 11 5 9 8 6 10 11 10 6 8 5 8 8 10 6 8.1 2.0
73 68 75 74 78 85 78 62 77 76 77 72 70 88 75 77 63 77 77 73 70 72 74.4 5.9
95 92 98 91 90 96 92 98 94 93 89 90 92 94 92 94 97 92 91 93 89 96 93.1 2.7
ASD, atrial septal defect; CHD, congenital heart disease; mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; PVRi, PVR index; Qp/Qs, pulmonary to systemic flow ratio; RAP, right atrial pressure; SpO2, systemic pulse oximetry; PaO2, pulmonary arterial O2 saturation; SVR, systemic vascular resistance; VSD, ventricular septal defect; WU, Wood units.
PAH may develop or become clinically manifest many years after shunt repair. There is currently very limited experience and no long-term data available in patients with borderline hemodynamics undergoing shunt closure to raise concerns about defining a procedure as successful after a short follow-up (months or a few years). Indeed, patients may deteriorate years after an initial short-term improvement [10]. Timely correction of the underlying congenital heart defect (i.e., early in childhood) can actually prevent the development of PAH–CHD. However, a certain proportion of patients with left-to-right shunts are not
recognized until later in life when changes in pulmonary vasculature and PVR have already occurred. Currently, there are no established markers of reversibility in this gray zone, although a number of candidates have been proposed. To date, the most promising marker seems to be the number of circulating endothelial cells. This is a non-invasive marker of vascular damage and remodeling, which has been shown to be significantly raised in CHD patients with irreversible PAH postsurgery [11]. Further studies are required to confirm whether this is an appropriate marker. There are no evidence-based algorithms to guide
Table 2 Hemodynamics of the study patients after shunt closure. Patient
CHD
Age (years)
Time delay (months)
Qp (l/min/m2)
RAP (mm Hg)
PVR (WU)
PVRi (WU* ∗ m2)
mPAP (mm Hg)
PCWP (mm Hg)
PaO2 (%)
SpO2 (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean SD
VSD ASD VSD VSD + ASD ASD ASD ASD AVC ASD ASD PDA ASD VSD ASD VSD ASD ASD ASD VSD VSD ASD ASD
9.2 37.7 22.4 25.4 60.2 49.2 52.1 28.2 60.1 31.2 12.2 61.2 8.1 72.0 5.0 61.0 49.2 37.7 22.4 8.2 49.2 52.1 37.0 20.8
46 67 184 265 59 251 98 254 44 227 40 54 49 358 57 108 278 67 186 40 242 110 140.2 100.3
3.8 2.5 3.1 3.9 3.2 3.4 3.0 1.9 1.7 2.5 1.9 2.7 1.8 2.3 2.8 2.8 4.1 2.5 2.2 3.2 2.3 2.5 2.7 0.7
4 5 7 8 14 5 15 28 15 28 20 9 15 3 5 12 5 5 7 4 5 15 10.6 7.4
7.4 4.6 13.2 14.7 4.4 7.8 3.5 22.9 8.9 18.4 38.3 2.9 15.0 4.9 20.4 4.8 5.8 4.6 18.6 8.8 10.5 5.0 11.2 8.6
10.8 7.1 19.4 23.6 7.8 12.4 5.7 38.9 17.1 26.9 31.3 4.8 26.7 7.3 19.6 8.2 9.3 7.1 27.3 12.8 17.0 8.0 15.9 9.7
46 25 67 100 35 50 30 85 38 80 68 26 60 26 62 34 50 25 67 46 50 30 50.0 21.4
5 7 7 8 10 8 13 11 9 14 8 13 12 9 7 11 12 7 7 5 11 10 9.3 2.6
80 73 75 85 82 82 63 60 65 65 68 72 60 69 62 80 82 73 75 80 82 63 72.5 8.3
97 96 98 97 96 96 95 89 88 96 86 95 85 91 94 93 97 93 97 96 87 98 93.6 4.1
ASD, atrial septal defect; CHD, congenital heart disease; mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; PVRi, PVR index; Qp/Qs, pulmonary to systemic flow ratio; RAP, right atrial pressure; PaO2, pulmonary arterial O2 saturation; SpO2, systemic pulse oximetry; SVR, systemic vascular resistance; VSD, ventricular septal defect; WU, Wood units.
Please cite this article as: D'Alto M, et al, Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.036
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M. D'Alto et al. / International Journal of Cardiology xxx (2013) xxx–xxx
Fig. 1. Pulmonary vascular resistance (PVR) expresses in Wood units (WU) at baseline and at follow-up.
assessment for operability in these patients, and decisions should be based on careful evaluation of the individual patient. There are several arguments both in favor and against repair of congenital heart defects in patients with still net left-to-right shunt and moderately high PVR [12]. On one hand, in these patients shunt closure may abort right-to-left shunting, reduce cerebrovascular events, prevent cyanosis and its consequences, and protect the pulmonary circulation. On the other hand, leaving these patients untreated may prevent progression of Eisenmenger physiology to idiopathic PAH (having a worse long-term outcome) while avoiding high-risk surgery. In addition, no long-term data are available in this setting. In the last years, there has been increasing interest in the potential for use of PAH-specific therapies in the so-called “treat-and-repair”
Table 3 Clinical follow-up data of the study patients after PAH diagnosis. Patient
CHD
WHO FC at last observation
Medications
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean SD
VSD ASD VSD VSD + ASD ASD ASD ASD AVC ASD ASD PDA ASD VSD ASD VSD ASD ASD ASD VSD VSD ASD ASD
2 2 3 1 2 2 3 – – – 2 2 – 2 3 2 3 – 3 1 3 3 2.3 0.7
bos bos amb bos sil bos bos bos bos bos sil bos bos sil bos sil bos bos amb bos bos bos
– – sil sil – sil sil sil sil sil – – sil – sil – sil – sil – sil sil
– – – epo – – – – – tre – – epo – – – – – – – – –
war war war war war war war – war war – war war war – war – war war war war war
Time from PAH diagnosis (years)
Outcome
3.1 3.2 5.4 8.2 4.5 6.1 6.5 7.2 6.2 2.6 1.4 7.4 1.8 6.8 3.5 3 2.3 3.6 5.4 1.2 4.2 5.6 4.4 2.1
A A A LTx A A A Dead Dead Dead A A Dead A A A A Dead A A A A
A, alive; ASD, atrial septal defect; amb, ambrisentan; bos, bosentan; CHD, congenital heart disease; epo, epoprostenol; LTx, lung transplantation; sil, sildenafil; VSD, ventricular septal defect; war, warfarin; WHO FC, World Health Organization functional class.
strategy aimed at reducing PVR, thus improving operability of patients with PAH–CHD. However, available data on closure of intra- or extra cardiac shunts in the presence of severe PAH, with or without the use of targeted PAH therapies (“treat-and-repair” approach), are scarce and still limited to case reports [13–17] or case series [10,18]. Initial results appear promising, but in most cases follow-up was relatively short, and the long-term adaptation of the right ventricle after correction of the congenital heart defect remains unknown. Consistent with other studies [2,19], the clinical course of PAH in previously repaired defects was not benign in our series, showing a high mortality rate (22% death and one lung transplantation over 4.4 years of follow-up). This observation raises concerns about repairing CHD in patients with overt PH or “borderline” hemodynamics, because their outcome may be worse with corrected than with uncorrected shunt, mainly as a consequence of the loss of the defect, which represents a “relief valve” for the right heart chambers. In conclusion, high baseline values of PVR (≥ 5 Wood units), PVRi (≥6 Wood units ∗ m2) and PVR/SVR (≥0.33) are common findings in patients who develop PAH after shunt closure. A Qp/Qs N 2 may be considered reassuring before shunt closure. PAH may develop or become clinically manifest years after shunt repair. The clinical course of PAH in previously repaired defects was not benign, showing a high mortality rate. However, owing to the limited amount of data, large prospective clinical trials are needed to establish the safe limits for shunt closure.
4.1. Limitations of the study This is a retrospective, single center study. The main limitation of this study is that it included only patients referred for PAH development, without allowing evaluation of patients with similar hemodynamics who had a favorable outcome. This is a strong bias against treatment of patients with “borderline” hemodynamics. However, the aims of this retrospective study were to assess baseline hemodynamics of patients who developed PAH after shunt closure and not to establish the safe limits for surgical or percutaneous correction. Another important study limitation is that the time delay between shunt closure and PAH diagnosis at follow-up RHC does not necessarily indicate the time for developing PAH, as, theoretically, each patient should manifest PAH immediately after shunt closure. Finally, a not negligible proportion of patients (8/30, 27%) developing PAH after shunt closure did not undergo baseline hemodynamic assessment.
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Please cite this article as: D'Alto M, et al, Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.036