Sildenafil reduces pulmonary vascular resistance in single ventricular physiology

International Journal of Cardiology 221 (2016) 122–127

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Sildenafil reduces pulmonary vascular resistance in single ventricular physiology Hiroki Mori, In-Sam Park, Hiroyuki Yamagishi, Makoto Nakamura, Shiro Ishikawa, Kiyohiro Takigiku, Satoshi Yasukochi, Tomotaka Nakayama, Tsutomu Saji, Toshio Nakanishi ⁎ Tokyo Women's Medical University, Pediatric Cardiology, 8-1, Tokyo

a r t i c l e

i n f o

Article history: Received 22 February 2016 Received in revised form 27 June 2016 Accepted 29 June 2016 Available online 02 July 2016

a b s t r a c t Background: High pulmonary vascular resistance (PVR) may be a risk factor for early and late mortality in both Glen shunt and Fontan operation patients. Furthermore, PVR may increase long after the Fontan operation. Whether pulmonary vasodilators such as phosphodiesterase 5 inhibitors can decrease PVR in patients with single ventricular physiology remains undetermined. Methods and results: This was a prospective, multicenter study. Patients with single ventricular physiology who have a PVR index higher than 2.5 Wood units·㎡ (WU) were enrolled. Cardiac catheterization was performed before and after administration of sildenafil in all patients. After the Fontan operation, a six minute walk test (6 MWT) was also performed. A total of 42 patients were enrolled. PVR was significantly decreased in each stage of single ventricular physiology after sildenafil administration: from 4.3 ± 1.5 WU to 2.1 ± 0.6 WU (p b 0.01) in patients before a Glenn shunt, from 3.2 ± 0.5 WU to 1.6 ± 0.6 WU (p b 0.001) in patients after a Glenn shunt, and from 3.9 ± 1.7 WU to 2.3 ± 0.8 WU (p b 0.001) in patients after Fontan. In patients after Fontan, the 6 MWT increased from 416 ± 74 m to 485 ± 72 m (p b 0.01), and NYHA functional class improved significantly (p b 0.05) after sildenafil administration. No major side effects were observed in any patients. Conclusions: Sildenafil reduced PVR in patients with single ventricle physiology. Sildenafil increased exercise capacity and improved NYHA functional class in patients after a Fontan operation. This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated PVR with single ventricle physiology. Long-term clinical significance warrants further study. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The Fontan procedure is the only procedure to eliminate cyanosis in patients with a functionally univentricular heart. In three decades, mortality and morbidity of the Fontan operation have improved dramatically [1,2]. The therapeutic strategy to perform a bidirectional Glenn shunt (a superior cavopulmonary shunt) before Fontan completion may be one of the major reasons for the improved rate of mortality [3,4]. Despite the changes in surgical strategy, relatively high pulmonary arterial pressure and pulmonary vascular resistance may still be risk factors of early and late mortality of both Glenn shunts and Fontan operations. There are several reports suggesting that a mean

⁎ Corresponding author at: Department of Pediatric Cardiology, Division of Clinical Research for Adult Congenital Heart Disease Life-Long Care and Pathophysiology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162, Japan. E-mail address: [email protected] (T. Nakanishi).

http://dx.doi.org/10.1016/j.ijcard.2016.06.322 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.

pulmonary arterial pressure N 15–18 mm Hg and pulmonary vascular resistance N2–4 Wood units·m2 are associated with increased mortality [5–7]. Amelioration of these factors may optimize postoperative management. Fontan circulation has a unique nature in that it lacks the ventricle to propel pulmonary blood flow. In long-term studies after a Fontan operation, various problems may become apparent, including exercise intolerance, liver dysfunction, protein-losing enteropathy, and arrhythmia [8]. These problems, emanating long after the Fontan operation, may result, at least in part, from increases in pulmonary vascular resistance (PVR), which in turn causes increases in pulmonary arterial pressure, right atrial enlargement, decreases in cardiac output, and liver congestion. Recently, several pulmonary vasodilators, including endothelin receptor antagonists, prostaglandin I2, and phosphodiesterase 5 inhibitors (PDE5i), have been introduced to treat idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with congenital heart disease. It, however, remains undetermined whether pulmonary

H. Mori et al. / International Journal of Cardiology 221 (2016) 122–127

vasodilators can decrease PVR in patients with single ventricular physiology [9]. Thus, a multicenter, single-arm study was conducted to determine whether sildenafil, PDE5i, reduces pulmonary vascular resistance before and after a Fontan operation. 2. Methods 2.1. Subjects This study was a prospective, open label, multicenter and single-arm study. Patients with single ventricular physiology between the ages of 1 and 50 years old who undertook cardiac catheterization, and had a PVR index (PVRi) higher than 2.5 Wood units·m2 (WU) were enrolled. These criteria were adopted in this study because a PVR N2.5 Wood units·m2 was considered higher than normal [10,11]. In patients after palliative or Fontan operation, cardiac catheterizations were performed more than six months after these operations. Patients were divided into three groups, according to clinical situations. Patients in Group 1 had not undergone any surgical intervention (including a Glenn shunt), except for a Blalock–Taussig shunt. Patients in Group 2 had received a bidirectional Glenn shunt, but not a Fontan operation. Patients in Group 3 had undergone a Fontan operation. A total of 42 patients were enrolled in this study (30 patients at Tokyo Women's Medical University, six at Sakakibara Heart Institute, four at Keio University, two at Nagano Children's Hospital, and none at Fukuoka Children's Hospital or Toho University). Group 1 included 7 patients, Group 2, 11, and Group 3, 24. Baseline characteristics are summarized in Tables 1 and 2. In Group 1, sildenafil was started at the age of 12 ± 8 months. Four patients had undergone Blalock–Taussig shunt operation. In Group 2, the Glenn procedure had been performed at 39 ± 82 (median 14) months of age, and sildenafil was started 44 ± 84 (median 9.8) months after the Glenn procedure. In Group 3, the mean age at the time of the Fontan operation was 3.6 ± 2.7 years old, and mean age of sildenafil administration was 9.5 ± 4.6 years after Fontan operation. Sildenafil was started at a dose of 0.5 mg per kilograms and increased to 1 to 2 mg per kilograms within 1–2 months. In adult patients N18 years old, sildenafil was started with a dose of 40 mg/day, and increased to 60 mg/day. Follow-up catheterizations for assessment of hemodynamics were performed three months after sildenafil administration in all patients. Mean pulmonary artery pressure (MPAP, in mm Hg), pulmonary blood flow (Qp, in L/min/m2), systemic blood flow (Qs, in L/min/m2) or cardiac index (CI, in L/min/m2), transpulmonary pressure gradient (TPPG, in mm Hg), and PVR index (PVRi, in Wood units·m2) were measured. CI and Qp were measured using the Fick method. The grade of atrioventricular valve regurgitation was assessed from ventriculography. In patients

123

Table 2 Baseline characteristics. ALL (n = 42)

Group 1 (n = 7)

Group 2 (n = 11)

Group 3 (n = 24)

Atrioventricular valve regurgitation None 25 Mild 11 Moderate 6 Severe 0

3 2 2 0

10 0 1 0

12 9 3 0

Medical therapy Furosemide Spironolactone Trichlormethiazide ACE inhibitors/ARB Carvedilol Digoxin Aspirin Warfarin Anti-arrhythmia drug Bosentan Beraprost sodium Home oxygen therapy

3 2 0 2 0 0 3 1 0 0 1 0

4 4 0 4 2 0 8 3 0 1 2 5

13 15 2 10 1 5 9 4 1 3 5 1

20 21 2 16 3 5 20 8 1 4 8 6

after the Glenn shunt, cardiac output and pulmonary blood flow were estimated using calculation method of Salim et al. [12]. Assessment of NYHA functional class and 6 MWT was performed to evaluate exercise capacity in Group 3 patients. All the following blood tests were performed at the time of cardiac catheterization: hemoglobin (Hb), creatinine (Cre), aspartate aminotransferase (AST), alanine aminotransferase (ALT), brain natriuretic peptide (BNP), and estimated glomerular filtration ratio (eGFR). Exclusion criteria for this study were as follows; 1: Existence of significant arteriopulmonary collateral vessels, 2: Existence of pulmonary artery stenosis and/or pulmonary vein obstruction, 3: Existence of respiratory failure and upper airway obstruction. The primary outcome investigated in this study was improvement of PVRi. Secondary outcomes in Groups 1 and 2 were whether they were able to proceed to the next surgical step, such as a Glenn shunt or Fontan operation. In Group 3, the secondary outcome was an improvement of exercise capacity and NYHA functional class.

Table 1 Patient characteristics.

Sex Male (n) Female (n) Height(cm) Weight (Kg) Age at administration (months or years) Months or years after final operation (years) Hb concentration (g/dL) O2 saturation (%) Anatomical diagnosis, n Tricuspid atresia Hypoplastic left heart syndrome Single ventricle Double outlet right ventricle PA-IVS Operation type (no. of patients, including overlap) No palliation prior to Glenn or Fontan Systemic to pulmonary shunt Pulmonary artery banding Norwood procedure Damus–Kaye–Stansel TAPVR repair Pulmonary artery angioplasty Atrio-ventricular valve plasty Pace maker implantation Glenn type Original Glenn Bidirectional Glenn Kawashima procedure Fontan type APC LT TCPC

All (n = 42)

Group 1 (n = 7)

Group 2 (n = 11)

Group 3 (n = 24)

18 24

5 2 67.4 ± 5.3 6.8 ± 1.2 12.0 ± 7.7 months 13.0 ± 8.5 months 16.4 ± 2.2 81.6 ± 5.1

3 8 98.7 ± 30.5 16.7 ± 12.0 6.9 ± 9.6 years 4.0 ± 7.2 years 16.7 ± 1.5 81.1 ± 4.6

10 14 135.9 ± 25.5 36.7 ± 17.0 12.7 ± 5.7 years 9.5 ± 4.6 years 15.9 ± 2.4 92.4 ± 4.05

5 2 8 19 8

1 1 2 2 1

1 0 1 4 5

3 1 5 13 2

3 2 3 1 0 0 0 0 0

0 8 4 0 3 0 2 0 0

2 16 4 1 1 1 6 3 2

– – –

0 10 1

0 6 1

– – –

– – –

12 2 10

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Fig. 1. Changes in pulmonary vascular resistance index (PVRi) before and after sildenafil administration. A: Group 1. PVR demonstrated a change from 4.3 ± 1.5 to 2.1 ± 0.6 WU·m2. B: Group 2. PVR demonstrated a change from 3.2 ± 0.5 to 1.6 ± 0.6 WU·m2. C: Group 3. PVR changed from 3.9 ± 1.7 to 2.3 ± 0.8 WU·m2. Pulmonary vascular resistance was significantly reduced after sildenafil administration in all groups. (*p b 0.01, **p b 0.001). Institutional research board approval was obtained from Tokyo Women's Medical University Hospital.

2.2. Statistical analysis Patient characteristics are represented as mean ± SD. All statistical assessments were performed using JMP® Pro-11.2.0. Changes from baselines and follow-up observations were analyzed with a Student paired t-test in continuous variables. Categorical data were analyzed with a Wilcoxon signed-rank test. Statistical significance of differences was assumed at a P value b 0.05.

3. Results 3.1. Primary outcome: effect of sildenafil on PVRi PVRi was significantly decreased in all groups: in G1 from 4.3 ± 1.5 WU to 2.1 ± 0.6 WU (p b 0.01), in G2 from 3.2 ± 0.5 WU to 1.6 ± 0.6 WU (p b 0.001), and in G3 from 3.9 ± 1.7 WU to 2.3 ± 0.8 WU (p b 0.001) (Fig. 1).

3.3. Other hemodynamic parameters Pulmonary blood flow was increased in all groups: from 3.7 ± 1.3 to 4.7 ± 1.8 L/min/m 2 (p b 0.05) in Group 1, from 2.0 ± 0.8 to 2.7 ± 1.0 L/min/m 2 (p b 0.05) in Group 2, and from 2.0 ± 0.6 to 2.4 ± 0.6 L/min/m2 (p b 0.01) in Group 3 (Fig. 2). Mean pulmonary artery pressure was decreased from 23.9 ± 8.8 to 16.3 ± 2.9 mm Hg (p b 0.05) in Group 1, from 12.5 ± 3.0 to 10.6 ± 2.2 mm Hg (p b 0.05) in Group 2, and from 15.9 ± 4.4 to 12.8 ± 3.0 mm Hg (p b 0.01) in Group 3 (Fig. 3). The transpulmonary pressure gradient was decreased from 14.7 ± 8.8 to 7.6 ± 2.9 mm Hg (p b 0.05) in Group 1, from 6.0 ± 2.0 to 3.4 ± 1.6 mm Hg (p b 0.01) in Group 2, and from 6.9 ± 3.2 to 4.7 ± 2.3 mm Hg (p b 0.01) in Group 3 (Fig. 4). Qs before and after sildenafil administration were not significantly different in Group 1, 3.9 ± 2.2 (before) and 4.2 ± 1.5 L/min/m2 (after), in Group 2, 3.2 ± 1.1 (before) and 3.5 ± 0.8 L/min/m2 (after), and in Group 3, 2.4 ± 0.7 (before) and 2.5 ± 0.7 L/min/m2 (after). The grade of atrio-ventricular valve regurgitation was unchanged, and oxygen saturation at rest was not changed after sildenafil administration (data not shown).

3.2. Secondary outcome In Group 1, all patients underwent the Glenn shunt with no mortality. In Group 2, all patients underwent the Fontan operation with no mortality. In Group 3, NYHA functional class was improved significantly (p b 0.05) after sildenafil administration. Six minute walk distance improved from 416 ± 74 m to 485 ± 72 m (p b 0.01) after sildenafil administration (Table 3). (See Table 4.)

Table 3 Functional changes after sildenafil. Fontan

Pre

Post

NYHA functional class (n) I II III IV 6 minute walk distance (m)

4 18 2 0 415.8 ± 74.2

8 14 1 0 485.0 ± 71.8

P value p b 0.05

p b 0.01

Table 4 Changes after sildenafil.

Height (cm) Body weight (kg) Oxygen saturation (%) Group 1 Group 2 Group 3 RBC (×104/μL) Hb (g/dL) Ht (%) AST (U/L) ALT (U/L) t-bil (mg/dL) Cre (mg/dL) eGFR (ml/min/m2) BNP (pg/ml)

Pre

Post

P value

114.2 ± 35.9 26.3 ± 18.5 86.4 ± 6.6 81.6 ± 5.2 81.4 ± 4.4 91.1 ± 4.5 529.5 ± 102.2 16.1 ± 2.1 47.6 ± 5.7 36.4 ± 18.0 27.6 ± 24.6 0.8 ± 1.4 0.46 ± 0.21 98.5 ± 22.9 73.5 ± 106.1

120.7 ± 34.3 29.3 ± 18.4 86.3 ± 7.71 78.6 ± 7.5 82.3 ± 4.3 92.0 ± 4.8 520.9 ± 111.9 15.7 ± 2.4 46.5 ± 6.92 33.7 ± 16.5 26.8 ± 24.6 1.1 ± 0.6 0.51 ± 0.22 97.1 ± 23.8 84.5 ± 157.4

p b 0.01 p b 0.01 p = 0.79 p = 0.27 p = 0.19 p = 0.16 p = 0.27 p = 0.17 p = 0.15 p = 0.06 p = 0.34 p = 0.24 p b 0.01 p = 0.58 p = 0.42

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Fig. 2. Changes in pulmonary blood flow (Qp) before and after sildenafil administration. A: Palliation group. Qp increased from 3.7 ± 1.3 L/min/m2 to 4.7 ± 1.8 L/min/m2 (p b 0.05). B: Glenn group. Qp increased from 2.0 ± 0.8 L/min/m2 to 2.7 ± 1.0 L/min/m2 (p b 0.05). C: Fontan group. Qp increased from 2.0 ± 0.6 L/min/m2 to 2.4 ± 0.6 L/min/m2 (p b 0.01) Qp significantly increased after sildenafil administration in all groups. (*p b 0.05, ** p b 0.01).

3.4. Blood chemistry

4. Discussion

BNP was unchanged after sildenafil administration (from 56 ± 5 pg/ml to 54 ± 59 pg/ml (Table 3). Serum creatinine showed a significant increase, but estimated GFR was unchanged. Liver function tests remained within normal limits in all patients.

This prospective study, for the first time, demonstrated that sildenafil can reduce pulmonary vascular resistance in patients before and after a Glenn shunt and after a Fontan operation. Sildenafil can also increase exercise capacity and improve NYHA functional class in patients after the Fontan operation.

3.5. Side effects

4.1. Pulmonary vasodilators before Fontan operation

All patients continued to take sildenafil during the study. For one patient after a Fontan operation, the dose of sildenafil was reduced (from 40 mg/day to 30 mg/day) due to dizziness. Other side effects were not observed in this study.

Relatively high pulmonary arterial pressure and pulmonary vascular resistance may be risk factors for early and late mortality in both Glenn shunts and Fontan operations. There are several reports suggesting that mean pulmonary arterial pressure N15–18 mm Hg and pulmonary

Fig. 3. Changes in mean pulmonary artery pressure (MPAP) before and after sildenafil administration. A: Palliation group. MPAP decreased from 23.9 ± 8.8 mm Hg to 16.3 ± 2.9 mm Hg (p b 0.05). B: Glenn group. MPAP decreased from 12.5 ± 3.0 mm Hg to 10.6 ± 2.2 mm Hg(p b 0.05). C: Fontan group. MPAP decreased from 15.9 ± 4.4 mm Hg to 12.8 ± 3.0 mm Hg (p b 0.01). Pulmonary artery pressure was significantly reduced after sildenafil administration in all groups. (*p b 0.05, **p b 0.01).

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Fig. 4. Changes in transpulmonary pressure gradient (TPPG) before and after sildenafil administration. A: Palliation group. TPPG decreased from 14.7 ± 8.8 mm Hg to 7.6 ± 2.9 mm Hg (p b 0.05). B: Glenn group. TPPG decreased from 6.0 ± 2.0 mm Hg to 3.4 ± 1.6 mm Hg (p b 0.01). C: Fontan group. TPPG decreased from 6.9 ± 3.2 mm Hg to 4.7 ± 2.3 mm Hg (p b 0.01) TPPG was significantly decreased after sildenafil administration in all groups. TPPG was lower than 12 mm Hg after sildenafil administration in all patients. (*p b 0.05, **p b 0.01).

vascular resistance N 2–4 Wood units·m2 are associated with increased mortality [5–7]. In the series of Chowdhury et al. [6], the mortality rate of the Fontan operation was 30% in patients with high pulmonary artery pressure (N18 mm Hg) and pulmonary vascular resistance (N2.0 Wood units·m2), while none in the lower pulmonary artery pressure group died. In the present study, patients before their Fontan operation were thought to be at most risk of requiring further surgical interventions due to their high PVRi. After sildenafil administration, PVRi was reduced and patients underwent the next step of the operation without mortality. Hirono et al. [13] administered bosentan in eight patients before a Fontan operation with high pulmonary resistance, and showed that bosentan reduced pulmonary vascular resistance in all patients. All patients underwent successful Fontan operations in their series. These studies suggest that pulmonary vasodilators may change pulmonary vascular resistance before a Fontan operation and improve outcomes in candidates for the Fontan operation. In these studies, however, patients were not randomized into groups with and without pulmonary vasodilators before the operation and, therefore, it remains unclear whether pulmonary vasodilators indeed resulted in their outcomes of Glenn and Fontan operations. 4.2. Pulmonary vascular resistance after Fontan operation High pulmonary arterial pressure in single ventricular physiology can be caused by vascular hypertone, micro-thromboembolism, and/ or retrograde high pressure from increased left atrial pressure. Kaza et al. [14] and Ridderbos et al. [15] showed that intimal thickness of the small pulmonary artery was increased over time after the Fontan operation. However, a previous study reported that pulmonary vascular resistance was elevated and nitrogen monoxide (NO) reduced pulmonary vascular resistance late after the Fontan operation [16]. Therefore, although some irreversible obstructive changes may exist in pulmonary vasculature, pulmonary vasodilators may be still effective for hypertonic pulmonary resistance in arteries long after the Fontan operation. 4.3. Effect of sildenafil after Fontan operation Sildenafil targets the endothelial NO pathway by inhibiting phosphodiesterase-5, increasing cGMP, and causing pulmonary vasodilation. Tunks et al. [17] studied the effect of intravenous sildenafil administration during catheterization in 9 children after a Fontan operation. They

showed pulmonary vascular resistance index decreased from 2.4 to 1.9 Wood Units·m2. Van De Bruaene et al. [18] and Giardini et al. [19] also showed that in adult patients after Fontan operations, acute administration of sildenafil reduced pulmonary resistance and increased cardiac output at rest and during exercise. These data suggest that there is a capacity for the pulmonary vasculature, at least acutely, to respond to phosphodiesterase-5 inhibitors. Morchi et al. [11] showed in a retrospective study of 6 patients with failing Fontan physiology and a mean pulmonary artery pressure N15 mm Hg and pulmonary vascular resistance N3.5 ± 1.0 Wood units·m2, that there was a significant decrease in pulmonary artery pressure and in pulmonary vascular resistance after several months of sildenafil treatment. In a double-blind, placebo-controlled trial in 27 children and young adults, with a mean age of 14.9 years, 11.3 years (mean) after Fontan operation, Goldberg et al. [20,21] showed improvement in myocardial performance index using echocardiography and ventilatory efficiency after 6 weeks of treatment with sildenafil. The present study is the first prospective trial measuring pulmonary vascular resistance during cardiac catheterization several months after sildenafil treatment. In the present study, sildenafil significantly reduced the pulmonary vascular resistance index and transpulmonary pressure gradient, and mean pulmonary artery pressure. Although the 6 minute walk distance and NYHA functional class improved, cardiac output remained unchanged after sildenafil administration. The reasons for this are not clear, but cardiac output during exercise might have been improved by chronic reduction of pulmonary vascular resistance [18], or there might have been some improvement in ventricular performance and/or ventilatory efficiency, as reported previously [20, 21]. Cardiac output was not measured during exercise at the time of catheterization in the present study. It must be noted that the present study consisted of patients with high PVR, which may result in failing Fontan physiology. The present study and the study of Morchi et al. [11] suggest that sildenafil indeed improved pulmonary hemodynamics in failing single ventricular physiology. Whether sildenafil improves the long-term prognosis in Fontan patients is yet to be clarified. 4.4. Effect of other pulmonary vasodilators after Fontan operation Advantages and disadvantages of other pulmonary vasodilators compared to sildenafil remain unclear. In the study of Hebert et al.

H. Mori et al. / International Journal of Cardiology 221 (2016) 122–127

[22], 75 adolescents and adults after a Fontan operation were randomized to 14 weeks of treatment with bosentan (an endothelin blocker), or a placebo. The study showed that bosentan improved exercise capacity, exercise time, and functional class. Similarly, Derk et al. [23] showed that in seven adult patients after a Fontan operation, bosentan improved 6-minute walk distance and MRI-derived resting cardiac output after administration being for 4 months. In contrast, Schuuring et al. [24] showed in randomized open label trials that 6 months of treatment on bosentan did not change exercise capacity in Fontan patients. Ovaert et al. [25] investigated the effect of bosentan in 10 patients with a failing Fontan circulation. After 12 weeks of bosentan treatment, the 6 min walk tests did not change significantly. Thus, the effect of bosentan remains controversial in Fontan patients. Since the mechanisms of pulmonary vasodilation in bosentan and sildenafil are different, there may be some difference between these drugs in the vasodilator effect in patients with Fontan physiology. Further study is required in order to reveal the differences of pulmonary vasodilators and the effect of combination therapy with these drugs [26].

[6]

[7]

[8] [9]

[10] [11]

[12]

[13]

4.5. Side effects Although there were no patients who showed elevation of liver enzymes after sildenafil administration, careful observation is required since liver fibrosis or cirrhosis may exist at baseline in patients late after a Fontan operation [27]. The small number of patients in the present study suggests that sildenafil is safe and well tolerated in single ventricular patients.

[14]

[15]

[16]

4.6. Limitations [17]

First, the number of patients was small, especially for Groups 1 and 2. Second, because this study was a single arm-study, we could not present the data about natural changes of PVR. Third, follow-up duration was relatively short and longer observation is mandatory. Further studies are warranted in larger numbers of patients in a randomized trial setting.

[18]

[19]

5. Conclusion [20]

In this prospective study, sildenafil reduced pulmonary vascular resistance in patients before and after a Glen shunt, and after a Fontan operation. Sildenafil increased exercise capacity and improved the NYHA functional class in patients after Fontan operations. This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated pulmonary resistance after Fontan operation. Long-term clinical significance warrants further study.

[21]

[22]

Conflict of interest This study was partially supported by a research grant H27-022 from Japanese Ministry of Health and Welfare, a research grant 16ek0109146h0002 from Japan Agency for Medical Research and Development, and grant-in-aid from Pfizer Inc. References [1] F. Fontan, E. Baudet, Surgical repair of tricuspid atresia, Thorax 26 (1971) 240–248. [2] C.G. DeGroff, Modeling the Fontan circulation: where we are and where we need to go, Pediatr. Cardiol. 29 (2007) 3–12, http://dx.doi.org/10.1007/s00246-007-9104-0. [3] R.D. Mainwaring, J.J. Lamberti, K. Uzark, The bidirectional Glenn procedure: palliation of the univentricular heart, Adv. Card. Surg. 5 (1994) 115–140. [4] N.D. Bridges, R.A. Jonas, J.E. Mayer, M.F. Flanagan, J.F. Keane, A.R. Castaneda, Bidirectional cavopulmonary anastomosis as interim palliation for high-risk Fontan candidates. Early results, Circulation 82 (1990) IV170–IV176. [5] T.M. Giglia, T. Humpl, Preoperative pulmonary hemodynamics and assessment of operability: is there a pulmonary vascular resistance that precludes cardiac

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