Targeted Therapies in Fontan Patients Due to Single Ventricle:Recent Advances_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LIDan ,  WANGXu

PICU, Pediatric Cardiac Center of Fu Wai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P. R. China;

Corresponding author：

WANGXu, Email: fwpicu@163.com

Keywords：

Fontan procedure; Vascular resistance; Sildenafil; Bosentan

DOI：

10.7507/1007-4848.20160260

Video：

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Abstract Full text Figures/Tables Video References Cited by

The success of staged Fontan palliation for patients with single ventricle is related to low pulmonary vascular resistance (PVR). The complications of high PVR in Fontan physiology are numerous, such as low exercise tolerance, low cardiac output, ventricular function failure and protein-losing enteropathy; eventually it leads to failing Fontan. Therefore, a low PVR is crucial in Fontan patients. Now, targeted therapies decreasing PVR has been an advanced research hotspot in Fontan patients. In this review we present an overview of the safety and efficacy of the therapy with bosentan or sildenafil on elevated pulmonary artery pressure and pulmonary vascular resistance in Fontan patients.

Citation： LIDan, WANGXu. Targeted Therapies in Fontan Patients Due to Single Ventricle:Recent Advances. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2016, 23(11): 1112-1116. doi: 10.7507/1007-4848.20160260 Copy

1.	Rao PS. Fontan operation: indications, short and long term outcomes. Indian J Pediatr, 2015, 82(12): 1147-1156.
2.	Goldberg DJ, Paridon ASM. Fontan circulation: the search for targeted therapy. Circulation, 2014, 130(23): 1999-2001.
3.	d'Udekem Y, Iyengar AJ, Cochrane AD, et al. The Fontan procedure: contemporary techniques have improved long-term outcomes. Circulation, 2007, 116(11 Suppl): I157-I164.
4.	Valente AM, Lewis M, Vaziri SM, et al. Outcomes of adolescents and adults undergoing primary Fontan procedure. Am J Cardiol, 2013, 112(12): 1938-1942.
5.	Tatum GH, Sigfusson G, Ettedgui JA, et al. Pulmonary artery growth fails to match the increase in body surface area after the Fontan operation. Heart, 2006, 92(4): 511-514.
6.	Rychik J, Goldberg DJ. Late consequences of the Fontan operation. Circulation, 2014, 130(17): 1525-1528.
7.	Ohuchi H, Yasuda K, Miyazaki A, et al. Haemodynamic characteri-stics before and after the onset of protein losing enteropathy in patients after the Fontan operation. Eur J Cardiothorac Surg, 2013, 43(3): e49-e57.
8.	Ciliberti P, Schulze-Neick I, Giardini A. Modulation of pulmonary vascular resistance as a target for therapeutic interventions in Fontan patients: focus on phosphodiesterase inhibitors. Future Cardiol, 2012, 8(2): 271-284.
9.	Yoshimura N, Yamaguchi M, Oka S, et al. Inhaled nitric oxide ther-apy after Fontan-type operations. Surg Today, 2005, 35(1): 31-35.
10.	Rhodes J, Ubeda-Tikkanen A, Clair M, et al. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstra-tion of concept. Int J Cardiol, 2013, 168(3): 2435-2440.
11.	Giordano R, Palma G, Poli V, et al. First experience with sildenafil after Fontan operation: short-term outcomes. J Cardiovasc Med (Hagerstown), 2015, 16(8): 552-555.
12.	Derk G, Houser L, Miner P, et al. Efficacy of endothelin blockade in adults with Fontan physiology. Congenit Heart Dis, 2015, 10(1): e11-e16.
13.	Park IS. Efficacy of pulmonary vasodilator therapy in patients with functionally single ventricle. Int Heart J, 2015, 56(Suppl): S26-S30.
14.	Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax, 1971, 26(3): 240-248.
15.	Nakano T, Kado H, Tatewaki H, et al. Results of extracardiac conduit total cavopulmonary connection in 500 patients. Eur J Cardiothorac Surg, 2015, 48(6): 825-832.
16.	Marc G. The Fontan circulation. Heart, 2005, 8(1): 26-30.
17.	Maurice B. Fontan and the pulmonary circulation: A potential role for new pulmonary hypertension therapies. Heart, 2010, 96(12): 911-916.
18.	Turkoz R, Celik M, Palaoglu E, et al. Easy fenestration technique for extracardiac fontan operation. World J Pediatr Congenit Heart Surg, 2015, 6(4): 551-552.
19.	Goldberg DJ, Shaddy RE, Ravishankar C, et al. The failing Fontan: etiology, diagnosis and management. Expert Rev Cardiovasc Ther, 2014, 9(6): 785-793.
20.	Gewillig M, Brown S C, Eyskens B, et al. The Fontan circulation: Who controls cardiac output? Interact Cardiovasc & Thorac Surg, 2009, 10(3): 428-433.
21.	Speed K. Overexpression of endothelin-1 and endothelin receptors in the pulmonary arteries of failed Fontan patients. Inter J Cardiol, 2012, 159(1): 34-39.
22.	Blok IM, van Riel AC, Mulder BJ, et al. Management of patients with pulmonary arterial hypertension due to congenital heart disease: recent advances and future directions. Expert Rev Cardiovasc Ther, 2015, 13(12): 1377-1392.
23.	Snarr BS, Paridon SM, Rychik J, et al. Pulmonary vasodilator therapy in the failing Fontan circulation: rationale and efficacy. Cardiol Young, 2015, 25(8): 1489-1492.
24.	Butts RJ, Chowdhury SM, Baker GH, et al. Effect of sildenafil on pressure-volume loop measures of ventricular function in fontan patients. Pediatr Cardiol, 2016, 37(1): 184-191.
25.	Van De Bruaene A, La Gerche A, Claessen G, et al. Sildenafil impro-ves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging, 2014, 7(2): 265-273.
26.	Tunks RD, Barker PC, Benjamin DK Jr, et al. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med, 2014, 15(1): 28-34.
27.	Alfred H, Ruth W, Jan M, et al. Predictors of sildenafil effects on exercise capacity in adolescents and adults with Fontan circulation. Clin Res Cardiol, 2014, 103(8): 641-646.
28.	Alfred H, Sohrab F, John H. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J, 2008, 29(13): 1681-1687.
29.	Morchi GS, Ivy DD, Duster MC, et al. Sildenafil increases systemic saturation and reduces pulmonary artery pressure in patients with failing Fontan physiology. Congenit Heart Dis, 2009, 4(2): 107-111.
30.	Goldberg DJ, Benjamin F, Mcbride MG, et al. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation, 2011, 123(11): 1185-1193.
31.	Fine N, Dias B, Shoemaker G, et al. Endothelin receptor antagonist therapy in congenital heart disease with shunt-associated pulmonary arterial hypertension: a qualitative systematic review. Can J Cardiol, 2009, 25(3): e63-e68.
32.	Derk G, An R, Aboulhosn J. Endothelin receptor antagonism in single ventricle physiology with fontan palliation: A systematic review and meta-analysis. Clin Trials Regulat Sci Cardiol, 2015, 4: 1-5.
33.	Anders H, Mikkelsen UR, Ulf T, et al. Bosentan improves exercise capacity in adolescents and adults after fontan operation: The TEMPO (treatment with endothelin receptor antagonist in fontan patients, a randomized, placebo-controlled, double-blind study measuring peak oxygen consumption) study. Circulation, 2014, 130(130): 2021-2030.
34.	Schuuring MJ, Vis JC, Van Dijk AP, et al. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail, 2013, 15(6): 690-698.
35.	Hebert A, Jensen AS, Idorn L, et al. The effect of Bosentan on exercise capacity in Fontan patients; rationale and design for the TEMPO study. Bmc Cardiovasc Disord, 2013, 13(1): 1-7.
36.	Apostolopoulou SC, Papagiannis J, Rammos S. Bosentan induces clinical, exercise and hemodynamic improvement in a pre-transplant patient with plastic bronchitis after Fontan operation. J Heart Lung Trans, 2005, 24(8): 1174-1176.
37.	尚小珂, 李艳萍, 柳梅, 等.内皮素受体拮抗剂对Fontan术后患者中远期预后的影响.中华心血管病杂志, 2013, 41(12): 1025-1028.
38.	Bowater SE, Weaver RA, Thorne SA, et al. The safety and effects of bosentan in patients with a fontan circulation. Congenit Heart Dis, 2012, 7(3): 243-249.
39.	Caroline O, Daisy T, Daniel D, et al. The effect of bosentan in patients with a failing Fontan circulation. Cardiol Young, 2009, 19(4): 331-339.
40.	张雅娟, 闫军, 李守军, 等.儿童Fontan术后应用降低肺动脉高压药物治疗有益吗?中国胸心血管外科临床杂志, 2015, 22(4): 306-310.

1. Rao PS. Fontan operation: indications, short and long term outcomes. Indian J Pediatr, 2015, 82(12): 1147-1156.
2. Goldberg DJ, Paridon ASM. Fontan circulation: the search for targeted therapy. Circulation, 2014, 130(23): 1999-2001.
3. d'Udekem Y, Iyengar AJ, Cochrane AD, et al. The Fontan procedure: contemporary techniques have improved long-term outcomes. Circulation, 2007, 116(11 Suppl): I157-I164.
4. Valente AM, Lewis M, Vaziri SM, et al. Outcomes of adolescents and adults undergoing primary Fontan procedure. Am J Cardiol, 2013, 112(12): 1938-1942.
5. Tatum GH, Sigfusson G, Ettedgui JA, et al. Pulmonary artery growth fails to match the increase in body surface area after the Fontan operation. Heart, 2006, 92(4): 511-514.
6. Rychik J, Goldberg DJ. Late consequences of the Fontan operation. Circulation, 2014, 130(17): 1525-1528.
7. Ohuchi H, Yasuda K, Miyazaki A, et al. Haemodynamic characteri-stics before and after the onset of protein losing enteropathy in patients after the Fontan operation. Eur J Cardiothorac Surg, 2013, 43(3): e49-e57.
8. Ciliberti P, Schulze-Neick I, Giardini A. Modulation of pulmonary vascular resistance as a target for therapeutic interventions in Fontan patients: focus on phosphodiesterase inhibitors. Future Cardiol, 2012, 8(2): 271-284.
9. Yoshimura N, Yamaguchi M, Oka S, et al. Inhaled nitric oxide ther-apy after Fontan-type operations. Surg Today, 2005, 35(1): 31-35.
10. Rhodes J, Ubeda-Tikkanen A, Clair M, et al. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstra-tion of concept. Int J Cardiol, 2013, 168(3): 2435-2440.
11. Giordano R, Palma G, Poli V, et al. First experience with sildenafil after Fontan operation: short-term outcomes. J Cardiovasc Med (Hagerstown), 2015, 16(8): 552-555.
12. Derk G, Houser L, Miner P, et al. Efficacy of endothelin blockade in adults with Fontan physiology. Congenit Heart Dis, 2015, 10(1): e11-e16.
13. Park IS. Efficacy of pulmonary vasodilator therapy in patients with functionally single ventricle. Int Heart J, 2015, 56(Suppl): S26-S30.
14. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax, 1971, 26(3): 240-248.
15. Nakano T, Kado H, Tatewaki H, et al. Results of extracardiac conduit total cavopulmonary connection in 500 patients. Eur J Cardiothorac Surg, 2015, 48(6): 825-832.
16. Marc G. The Fontan circulation. Heart, 2005, 8(1): 26-30.
17. Maurice B. Fontan and the pulmonary circulation: A potential role for new pulmonary hypertension therapies. Heart, 2010, 96(12): 911-916.
18. Turkoz R, Celik M, Palaoglu E, et al. Easy fenestration technique for extracardiac fontan operation. World J Pediatr Congenit Heart Surg, 2015, 6(4): 551-552.
19. Goldberg DJ, Shaddy RE, Ravishankar C, et al. The failing Fontan: etiology, diagnosis and management. Expert Rev Cardiovasc Ther, 2014, 9(6): 785-793.
20. Gewillig M, Brown S C, Eyskens B, et al. The Fontan circulation: Who controls cardiac output? Interact Cardiovasc & Thorac Surg, 2009, 10(3): 428-433.
21. Speed K. Overexpression of endothelin-1 and endothelin receptors in the pulmonary arteries of failed Fontan patients. Inter J Cardiol, 2012, 159(1): 34-39.
22. Blok IM, van Riel AC, Mulder BJ, et al. Management of patients with pulmonary arterial hypertension due to congenital heart disease: recent advances and future directions. Expert Rev Cardiovasc Ther, 2015, 13(12): 1377-1392.
23. Snarr BS, Paridon SM, Rychik J, et al. Pulmonary vasodilator therapy in the failing Fontan circulation: rationale and efficacy. Cardiol Young, 2015, 25(8): 1489-1492.
24. Butts RJ, Chowdhury SM, Baker GH, et al. Effect of sildenafil on pressure-volume loop measures of ventricular function in fontan patients. Pediatr Cardiol, 2016, 37(1): 184-191.
25. Van De Bruaene A, La Gerche A, Claessen G, et al. Sildenafil impro-ves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging, 2014, 7(2): 265-273.
26. Tunks RD, Barker PC, Benjamin DK Jr, et al. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med, 2014, 15(1): 28-34.
27. Alfred H, Ruth W, Jan M, et al. Predictors of sildenafil effects on exercise capacity in adolescents and adults with Fontan circulation. Clin Res Cardiol, 2014, 103(8): 641-646.
28. Alfred H, Sohrab F, John H. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J, 2008, 29(13): 1681-1687.
29. Morchi GS, Ivy DD, Duster MC, et al. Sildenafil increases systemic saturation and reduces pulmonary artery pressure in patients with failing Fontan physiology. Congenit Heart Dis, 2009, 4(2): 107-111.
30. Goldberg DJ, Benjamin F, Mcbride MG, et al. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation, 2011, 123(11): 1185-1193.
31. Fine N, Dias B, Shoemaker G, et al. Endothelin receptor antagonist therapy in congenital heart disease with shunt-associated pulmonary arterial hypertension: a qualitative systematic review. Can J Cardiol, 2009, 25(3): e63-e68.
32. Derk G, An R, Aboulhosn J. Endothelin receptor antagonism in single ventricle physiology with fontan palliation: A systematic review and meta-analysis. Clin Trials Regulat Sci Cardiol, 2015, 4: 1-5.
33. Anders H, Mikkelsen UR, Ulf T, et al. Bosentan improves exercise capacity in adolescents and adults after fontan operation: The TEMPO (treatment with endothelin receptor antagonist in fontan patients, a randomized, placebo-controlled, double-blind study measuring peak oxygen consumption) study. Circulation, 2014, 130(130): 2021-2030.
34. Schuuring MJ, Vis JC, Van Dijk AP, et al. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail, 2013, 15(6): 690-698.
35. Hebert A, Jensen AS, Idorn L, et al. The effect of Bosentan on exercise capacity in Fontan patients; rationale and design for the TEMPO study. Bmc Cardiovasc Disord, 2013, 13(1): 1-7.
36. Apostolopoulou SC, Papagiannis J, Rammos S. Bosentan induces clinical, exercise and hemodynamic improvement in a pre-transplant patient with plastic bronchitis after Fontan operation. J Heart Lung Trans, 2005, 24(8): 1174-1176.
37. 尚小珂, 李艳萍, 柳梅, 等.内皮素受体拮抗剂对Fontan术后患者中远期预后的影响.中华心血管病杂志, 2013, 41(12): 1025-1028.
38. Bowater SE, Weaver RA, Thorne SA, et al. The safety and effects of bosentan in patients with a fontan circulation. Congenit Heart Dis, 2012, 7(3): 243-249.
39. Caroline O, Daisy T, Daniel D, et al. The effect of bosentan in patients with a failing Fontan circulation. Cardiol Young, 2009, 19(4): 331-339.
40. 张雅娟, 闫军, 李守军, 等.儿童Fontan术后应用降低肺动脉高压药物治疗有益吗?中国胸心血管外科临床杂志, 2015, 22(4): 306-310.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Targeted Therapies in Fontan Patients Due to Single Ventricle:Recent Advances

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