The challenge of managing pulmonary arterial hypertension in adults with congenital heart disease

Figures & data

Figure 1. The prostacyclin, nitric oxide and endothelin pathways.

Prostacyclin (PGI₂) is synthesized from arachidonic acid by COX-1 and PGI₂ synthase. PGI₂ activates the receptor of smooth muscle cells and in turn activates adenylate cyclase. This leads to increased production of cAMP from ATP with the effect of vasodilation and antiproliferation. Endothelial nitric oxide (NO) synthase produces NO from l-arginine. NO stimulates soluble guanylate cyclase resulting in increased production of cyclic guanylate monophosphate and thus antiproliferation and vasodilation. Preproendothelin is converted to big-endothelin (ET)-1 and subsequently ET-1 by furin-like enzyme and ET-converting enzymes, respectively. ET-1 activates ET-A and ET-B receptors, leading to calcium release and activation of protein kinase C, which leads to vasoconstriction and proliferation of smooth muscle cells.

Table 1. Currently available studies assessing disease targeting therapies in pulmonary arterial hypertension associated with congenital heart disease and selected studies of mixed pulmonary arterial hypertension populations.

Study (year)	Study population (n; % with CHD^†)	Study design	Outcome (primary outcome in RCTs)	Change in 6MWD	Follow-up period	Medication	Ref.
Rosenzweig et al. (1999)	CHD (20)	Retrospective	N/A	+52 m	1 year	Epoprostenol	[49]
Olschewski et al. for AIR (2002)	PAH (203; 0)	Randomized, double-blind, placebo-controlled	6MWD	+36 m	16 weeks	Inhaled iloprost	[51]
Rubin et al. for BREATHE-1 (2002)	PAH (213; 0)	Randomized, double-blind, placebo-controlled	6MWD	+44 m	16 weeks	Bosentan	[72]
Simonneau et al. (2002)	PAH (470; 23)	Randomized, double-blind, placebo-controlled	6MWD	+16 m	12 weeks	Treprostinil	[50]
Fernandes et al. (2003)	EES (8)	Retrospective	N/A	+299 m	3 months	Epoprostenol	[48]
Christensen et al. (2004)	CHD (9)	Retrospective	N/A	Not reported	9.5 months	Bosentan	[73]
Barst et al. for STRIDE-1 (2004)	PAH (178; 24)	Randomized, double-blind, placebo-controlled	Peak VO2	+35 m (100-mg dose)/+33 m (300-mg dose)	12 weeks	Sitaxsentan	[74]
Schulze-Neick et al. (2005)	CHD (33)	Open label prospective	WHO/6MWD	+72 m	2.1 years	Bosentan	[62]
Gatzoulis et al. (2005)	ES (10)	Open label prospective	SpO2 and 6MWD	+99 m	3 months	Bosentan	[75]
Galie et al. for SUPER-1 (2005)	PAH (278; 7)	Randomized, double-blind, placebo-controlled	6MWD	+45 m (20-mg dose)/+46 m (40-mg dose)/+50 m (80-mg dose)	12 weeks	Sildenafil	[22]
Galie et al. for BREATHE 5 (2006)	ES (54)	Randomized, double-blind, placebo-controlled	SpO2 and 6MWD	+43 m	16 weeks	Bosentan	[55]
Kotlyar et al. (2006)	ES (23)	Retrospective	N/A	No improvement	15 months	Bosentan	[76]
Benza et al. (2006)	CHD (24)	Retrospective	N/A	+31 m	1 year	Bosentan	[77]
Sitbon et al. (2006)	CHD (27)	Retrospective	N/A	+66 m	15 months	Bosentan	[78]
Mukhopadhyay et al. (2006)	ES (16)	Observational prospective	Hemodynamics/SpO2/WHO/6MWD	+43 m	12 weeks	Tadalafil	[64]
Singh et al. (2006)	ES (10)	Randomized, placebo-controlled, double-blind crossover	6MWD	+98 m	1.5 months	Sildenafil	[79]
Barst et al. for STRIDE-2 (2006)	PAH (245; 11)	Randomized, double-blind, placebo-controlled	6MWD	+24 m (50-mg dose)/+31 m (100-mg dose)	18 weeks	Sitaxsentan	[80]
D’Alto et al. (2007)	CHD (22)	Open label prospective	WHO/hemodynamics/6MWD	+67 m	1 year	Bosentan	[81]
Apostolopoulou et al. (2007)	CHD (18)	Open label prospective	SpO2 and 6MWD	No improvement at 2 years	2 years	Bosentan	[82]
Diller et al. (2007)	CHD (18)	Retrospective	N/A	+79 m	29 months	Bosentan	[83]
van Loon et al. (2007)	CHD (30)	Retrospective	N/A	No improvement	2.7 years	Bosentan	[58]
Chau et al. (2007)	ES (7)	Prospective open-label	WHO/SpO2/hemodynamics	+28 m (ES)	6 months	Sildenafil	[84]
Gatzoulis et al. For BREATHE-5 OLE (2008)	ES (37)	Open label extension of BREATHE 5	6MWD	+61 m	40 weeks	Bosentan	[56]
Galiè et al. for ARIES-1 and ARIES (2008)	PAH (394; 0)	Randomized, double-blind, placebo-controlled	6MWD	+51 m (10-mg dose)/+59 m (5-mg dose)	12 weeks	Ambrisentan	[85]
Galiè et al. for PHIRST (2009)	PAH (405; 12)	Randomized, double-blind, placebo-controlled	6MWD	+33 m (40-mg dose)	16 weeks	Tadalafil	[86]
Duffels et al. (2009)	CHD (58)	Retrospective	6MWD/QoL	Non-DS patients: +34m at 6 months and stable compared to baseline at 22 months DS patients: no improvement	22 months	Bosentan	[87]
Dimopoulos et al. (2010)	ES (68)	Retrospective	Survival	N/A	4 years	Bosentan, sildenafil, epoprostenol	[68]
Kermeen et al. (2010)	CHD (53)	Prospective, open-label, uncontrolled	SpO2/WHO/6MWD	+73 m	24 months	Bosentan, sitaxentan	[88]
Lu et al. (2010)	CHD (60)	Prospective, open-label, uncontrolled	6MWD/WHO/ hemodynamics	+51 m	12 weeks	Sildenafil	[89]
Vis et al. (2011)	CHD (64)	Prospective, open-label, uncontrolled	6MWD/QoL/WHO/survival	Non-DS patients: +36 m at 2.5 years. After that, no improvement	4 years	Bosentan	[59]
D’Alto et al. (2011)	CHD (74)	Prospective, open-label, uncontrolled	WHO/SpO2/6MWD/hemodynamics	Non-DS patients: +46 m DS patients: +49 m	12 months	Bosentan	[90]
Zeng et al. (2011)	CHD (ASD: 15; VSD: 24; PDA: 16)	Prospective, open-label, uncontrolled	6MWD/hemodynamics/WHO/Borg	At least +37 m in all groups; no difference observed	12 weeks	Sildenafil	[91]
Monfredi et al. (2011)	CHD (38; ES: 35)	Retrospective	6MWD/SpO2	Non-DS patients: +54 m	2.1 years	Bosentan	[92]
D’Alto et al. (2012)	CHD (32)	Prospective, open-label, uncontrolled	6MWD/WHO/Borg scale/hemodynamics	+33 m	6 months	Sildenafil addition to Bosentan	[66]
Dong et al. (2012)	CHD (31)	Prospective, randomized	MPAP/WHO/systolic function	N/A	12 months	Alprostadil	[93]
Diller et al. (2012)	ES (79)	Retrospective	6MWD/WHO	+50 m	3.3 years	DTT	[60]

^†The percentage of patients with CHD included in the study is provided in brackets where applicable.

6MWD: 6-min walking distance; ASD: Atrial septal defects; CHD: Congenital heart disease; DS: Down’s syndrome; DTT: Disease-targeting therapies; ES: Eisenmenger syndrome; MPAP: Mean pulmonary arterial pressure; NA: Not applicable; PDA: Patent ductus arteriosus; QoL: Quality of life; RCT: Randomized controlled trial; SpO₂: Arterial oxygen saturation; VSD: Ventricular septal defects.

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