Duration of right ventricular contraction predicts the efficacy of bosentan treatment in patients...

Pulmonary Arterial Hypertension in adult patients with Congenital Heart DiseasePulmonary Arterial Hypertension in adult patients with Congenital Heart Disease

Pulmonary Arterial Hypertension in adult patients with Congenital Heart Disease

Pulmonary Arterial Hypertension in adult patients with Congenital Heart Disease

Mariëlle Gea Joanna Duffels

Pulmonary Arterial Hypertension i n a d u l t p a t i e n t s w i t h Congen i ta l Hear t D i sease

Pulmonary Arterial Hypertension in adult patients w

ith Congenital Heart Disease Mariëlle G

ea Joanna Duffels 2009

boekenkaft_marielle_v8.indd 1 13-8-2009 16:16:08

Pulmonary arterial hypertension inadult patients with congenital heart disease


proefschrift duffels.indb 1 14-8-2009 16:41:18

Pulmonary Arterial Hypertension in adults with Congenital Heart DiseaseThesis, University of Amsterdam, the Netherlands

Cover Nicole Tirion, Erwin Nederstigt & Suzanne Blankhart, Styles conceptsLay out Chris Bor, AMCPrinted by Ponsen & Looijen

Financial support by the Netherlands Heart Foundation for the publication of this thesis is gratefully acknowledged.

Additional financial support for the printing of this thesis was provided by: Actelion Pharmaceuticals Nederland BV, Astellas Pharma, Boehringer Ingelheim bv, Daiichi Sankyo Nederland BV, GlaxoSmithKline BV, ICIN, Pfizer bv, Schering-Plough Nederland BV, Servier Nederland farma BV, Solvay Pharmaceuticals, Stichting Amstol, Tefa, University of Amsterdam.


Pulmonary arterial hypertension inadult patients with congenital heart disease

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctoraan de Universiteit van Amsterdamop gezag van de Rector Magnificus

prof. dr. D.C. van den Boomten overstaan van een door het college voor promoties

ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel

op vrijdag 30 oktober 2009, te 14.00 uur

door


geboren te Zaandam


PromotiecommissiePromotores Prof. dr. B.J.M. Mulder Prof. dr. R.M.F. Berger

Co-promotor Dr. P. Bresser

Overige leden Prof. dr. W. Budts Prof. dr. R.J.G. Peters Prof. dr. P.J. Sterk Prof. dr. J.G.P. Tijssen Dr. F.J. Meijboom Dr. A. Vonk Noordegraaf

Faculteit der Geneeskunde


ContentsChapter 1 Introduction and outline of the thesis

Published in part in Touch Briefings, European Cardiology 2008; 4 (1): 86-88

7

Chapter 2 Pulmonary arterial hypertension in congenital heart disease: An epidemiologic

perspective from a Dutch registry.

Int J Cardiol 2007 Aug 21; 120 (2):198-204.

19

Chapter 3 Pulmonary arterial hypertension in adults born with a heart septal defect: The

Euro Heart Survey on adult congenital heart disease.

Heart 2007; 93:682-687.

35

Chapter 4 Pulmonary arterial hypertension associated with a congenital heart defect:

Advanced medium-term medical treatment stabilizes clinical condition.

Congenital Heart Disease 2007; 2:242-249.

49

Chapter 5 Long-term effect of bosentan in adults versus children with pulmonary arterial

hypertension associated with systemic-to-pulmonary shunt: Does the beneficial

effect persist?

Am Heart J; 2007, 154:776-82.

61

Chapter 6 Down patients with Eisenmenger syndrome: Is bosentan treatment an option?

Int J Cardiol. 2009;134:378-83.

77

Chapter 7 Effect of bosentan on exercise capacity and quality of life in adults with

pulmonary arterial hypertension associated with congenital heart disease with

and without Down’s syndrome.

Am J Cardiol. 2009; 103:1309-1315.

89

Chapter 8 Bosentan in patients with pulmonary arterial hypertension: A comparison between

congenital heart disease and chronic pulmonary thromboembolism.

Neth Heart Journal 2009; 9: 334-338.

101

Chapter 9 Why six-minute walk test is not an appropriate endpoint in mildly symptomatic

pulmonary hypertension patients.

Based on Lancet 2008; 372: 1730.

111

Chapter 10 Duration of right ventricular contraction predicts the efficacy of bosentan

treatment in patients with pulmonary hypertension?

Eur J Echocardiogr. 2009;10:433-8.

121

Chapter 11 Atherosclerosis in patients with cyanotic congenital heart disease.

Submitted

133

Chapter 12 Summary & Samenvatting 145

Dankwoord 155

Curriculum vitae 161


11Chapter 1 Introduction

Pulmonary arterial hypertension in adults with congenital heart disease

Mariëlle GJ Duffels, Eric Boersma, Barbara JM Mulder

European Cardiology 2008; 4 (1): 86-88


Patients with congenital heart disease may develop pulmonary arterial hypertension (PAH) as the result of a left-to-right shunt. PAH causes decreased functional capacity, right ventricular failure, and is associated with early death. The final stage of PAH is called the Eisenmenger syndrome. Improved understanding of underlying pathophysiological mechanisms, and the introduction of new medical treatment strategies are bound to improve quality of life, morbidity and mortality in these patients, In this review the current state of PAH associated with congenital heart disease is summarized.

IntroductionCongenital heart disease is the most common congenital malformation and accounts for about 8 cases per 1000 births.1 Due to the tremendous developments of cardiac surgery, nearly 90% of all children with congenital heart disease reach adult age. In patients with congenital heart disease pulmonary arterial hypertension (PAH) may sooner or later develop due to increased pulmonary arterial flow as a result of a left-to-right shunt. PAH may lead to a decreased functional capacity and right ventricular failure, and is often associated with early death. Eisenmenger syndrome is at the severe end of the spectrum of PAH, characterised by severe irreversible PAH and reversal of the shunt leading to cyanosis, initially during exercise and, at a later stage, at rest. The Eisenmenger syndrome involves about 1% of all patients with congenital heart disease.2 In this review we will summarize the current state of PAH associated with congenital heart disease and the Eisenmenger syndrome.

Development of pulmonary arterial hypertensionPAH is defined as an elevated mean pulmonary arterial pressure of > 25 mmHg at rest or > 30 mmHg on exercise, measured during right heart catheterisation.3 The development of PAH is usually the result of an excessive pulmonary blood flow due to a left-to-right shunt and is related to the size, type and dimensions of the defect and the correction status.2, 4, 5 Chronic exposure of the pulmonary vasculature to increased blood flow may induce vasoconstriction and structural changes i.e. intimal fibrosis, medial hypertrophy, and increased production of extracellular matrix in the adventitia. The structural changes result in increased pulmonary vascular resistance and PAH. These changes may ultimately lead to a reversal of the systemic-to-pulmonary shunt accompanied by cyanosis, the so-called Eisenmenger syndrome.6 Figure 1 shows a cardiac MR image of a patient with Eisenmenger syndrome.

Various congenital heart defects may lead to PAH or Eisenmenger syndrome such as univentricular heart, truncus arteriosus, patent ductus arteriosus, septal defects or surgical shunts (Potts, Waterston, Blalock-Taussig).7 By far the largest proportion of patients with PAH have a septal defect, such as ventricular septal defect, primum or secundum atrial septal defect or complete atrioventricular septal defect.7 Early closure of the defect may prevent the subsequent development of PAH.8

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Epidemiology

Until recently, the prevalence of PAH in patients with congenital heart disease was not known. Two databases on adult congenital heart disease have recently been analyzed on the prevalence of PAH among these patients. The CONCOR (CONgenital COR vitia) registry is a nationwide registry of adult patients with congenital heart disease in the Netherlands that was designed to study the epidemiology and late outcome of congenital heart disease and includes adult patients with structural congenital heart disease from both referral and regional hospitals.9 Data analyzed from the CONCOR registry showed a prevalence of PAH of 4.2% (n=248) among all 5970 registered adult patients. Of 1824 patients with a septal defect in the registry, 6.1% (n=112) had PAH. Among the 899 patients with a previously closed septal defect, 3.3% (n=30) had PAH. The Eisenmenger syndrome involved about 1.1% of all patients with congenital heart disease.2

A higher prevalence of PAH was found in the Euro Heart Survey; PAH was present in 531 (28%) of the 1877 patients. However, this survey contained only data of adult patients with one of eight selected congenital heart defects from 26 countries and 79 centres (61% tertiary centres) throughout Europe.10 In the Euro Heart Survey, PAH was unexpectedly common, which was probably due to the large number of patients who attended a referral centre (83%) or who were referred for closure of the defect (35%).7 In summary, data from these two large

Figure 1. Cardiac MR image, oblique sagittal view, of a patient with Eisenmenger syndrome due to a ventricular septal defect (*). Arrow indicates the right ventricular hypertrophy. Note the dilated pulmonary artery (PA) with a small regurgitant jet. LV=left ventricle, RV=right ventricle.10


databases indicate that PAH is a risk factor in the long-term clinical course of septal defects with a prevalence of at least 6%.

Ventricular septal defect is the most frequent underlying defect (42%) among patients with PAH in the CONCOR registry. The median age of the CONCOR patients with PAH is 38 years (range 18-81 years) and 60% of them are women.2 PAH increases with age and is associated with a worse functional class and an enhanced risk of death, particularly among patients with Eisenmenger syndrome.7

Clinical presentation

Clinical signs of PAH are variable and depend on the underlying congenital heart disease, patient age, repair status, and degree and direction of shunting. Symptoms are related to a reduced cardiac output, congestive heart failure, arrhythmias, and hypoxemia and may affect quality of life, morbidity and mortality. General symptoms suggestive of PAH are non-specific and may include dyspnea, chest pain, peripheral oedema, and syncope.3 In patients with Eisenmenger syndrome, central cyanosis and clubbing are the most visible clinical consequences. However, it should be emphasized that not all Eisenmenger patients are cyanotic at rest.

In cyanotic patients, compensatory mechanisms to maintain adequate tissue oxygenation take place. Chronic cyanosis results in elevated renal production of erythropoietin thus promoting erythropoiesis and secondary erythrocytosis.11 Repeated phlebotomies in cyanotic patients with congenital heart disease and PAH induce iron deficiency and should be abandoned. Iron deficiency has been associated with an increased risk of cerebrovascular events in cyanotic adults.12 Phlebotomy is indicated only for symptomatic hyperviscosity syndrome and should be performed with simultaneous isovolumic fluid replacement, to avoid a catastrophical collaps. In patients with Eisenmenger syndrome one or more of the following non-cardiac complications may occur: bleeding, thrombotic diathesis, endocarditis or cerebral abscess, and impaired hepatic- and renal function.13 Therefore, Eisenmenger syndrome can be considered as a multisystem disorder.

Prognosis

In patients with Eisenmenger syndrome, mortality is high; 21% died during the 5-year follow-up period of the Euro Heart Survey.7 General prognosis is related both to the severity of PAH and to the underlying congenital heart disease. Variables associated with a poor long-term outcome are syncope, elevated right heart filling pressure, severe hypoxemia, and Down syndrome.4, 14 PAH is a progressive condition and patients usually die between the third and fifth decade of life; in patients with Eisenmenger syndrome median survival is reduced by approximately 20 years compared to healthy individuals.13 Around 55 to 63% of patients with Eisenmenger syndrome die of sudden cardiac death; other frequent causes of death include congestive heart failure, hemoptysis, brain abscess, thromboembolism, and complications of pregnancy or non-cardiac surgery.15, 16 Survival of patients with Eisenmenger syndrome

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however, is far better than the median survival of 2.8 years of patients with idiopathic pulmonary arterial hypertension.17, 18

New developments in medical treatment strategies

Once the Eisenmenger syndrome is present, surgical closure of the defect is no longer an option. The right ventricle will be unable to generate enough pressure to overcome the high pulmonary vascular resistance and will decompensate. Until recently, treatment options for patients with PAH associated with congenital heart disease were limited to the avoidance and treatment of complications. Because natural survival prospects are far better compared with idiopathic or other forms of PAH, heart-lung transplantation is restricted to highly symptomatic patients and those in whom life expectancy is considered short.

In the last decade, new medical treatment strategies have demonstrated to be beneficial in patients with PAH.18-20 Recent studies have shown short-term positive treatment effects of intravenous prostacyclin, endothelin receptor antagonist and phosphodiesterase-5-inhibitors in patients with PAH associated with congenital heart disease.20-29 In figure 2 the different

Figure 2. The different pathways for medical treatment of pulmonary arterial hypertension.

12


pathways for this medical treatment of PAH are shown. Prostacyclin or epoprostenol is a potent short-acting vasodilator and inhibitor of platelet aggregation produced by the vascular endothelium. In patients with PAH, the synthesis of prostacyclin is markedly diminished in the pulmonary endothelium. However, prostacyclin therapy is complicated by the need for continuous intravenous infusion or frequent nebulizers.21 Bosentan inhibits the endothelin A and B receptors, and competes with endothelin-1 which usually binds to those receptors. Endothelin-1 is a potent vasoconstrictor and a mitogen for vascular smooth muscle cells and fibroblasts. Overexpression of endothelin-1 has been demonstrated in the pulmonary vasculature of patients with PAH. By blocking endothelin receptors type A and B, bosentan may decrease endothelin-related vasoconstriction and smooth cell proliferation, and thus modify functional and structural changes in the pulmonary vessels. Phosphodiesterase-5 is abundantly expressed in the lung where it inactivates cyclic guanosine monophosphate (cGMP), thereby inhibiting the vasodilatory effects of nitric oxide and atrial natriuretic peptides. The phosphodiesterase-5-inhibitor, sildenafil, causes relaxation of pulmonary vascular smooth muscles by activating large-conductance, calcium-activated potassium channels.30

Endothelin receptor antagonists inhibits endothelin receptors type A and B and may decrease endothelin-related vasoconstriction and smooth cell proliferation. Phosphodiesterase-5 inhibitors cause relaxation of pulmonary vascular smooth muscles by activating calcium-activated potassium channels. Prostacyclin is a potent short-acting vasodilator and inhibitor of platelet aggregation produced by the vascular endothelium. (From: Humbert M, Sitbon O, Simonneau. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004; 351:1425-36.)

New medical treatment strategies are promising; however, experience in adults with congenital heart disease is limited; no long-term survival benefits following new medical treatment strategies have been demonstrated, yet. Despite therapy, the clinical condition may deteriorate. In such situations combination therapy may improve outcome in patients with PAH. However, studies to assess the effect of combination treatments are lacking.

Future perspective

Surgical correction of the underlying congenital heart defect during childhood, before the characteristic changes in the pulmonary arteries have started to appear, will mostly prevent the development of PAH and its severe form, the Eisenmenger syndrome.31, 32 Due to improved diagnostic and treatment strategies, the prevalence of PAH could be expected to decline. However, the increased prevalence of PAH with age, makes a strong decline in PAH prevalence unlikely.

Improved understanding of the underlying pathophysiological mechanisms, careful medical management, and the introduction of new medical treatment strategies are bound to improve quality of life and long-term survival prospects for patients with PAH and congenital heart disease.

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Outline of the thesis

In the studies described in this thesis we focus on adult patients with PAH due to left-to-right shunting associated with congenital heart disease. This chapter, chapter 1 is used as an introduction on the issues discussed in the subsequent chapters.

Although PAH may occur in the context of a wide range of different defects, the great majority of patients with PAH have a congenital heart defect as underlying defect. However, the actual prevalence of PAH in this patient group remained unknown. Therefore, we determine the prevalence of PAH due to congenital heart disease in chapter 2 by using data from the CONCOR (CONgenital COR vitia) registry, a nationwide registry of adult patients with congenital heart disease in the Netherlands. Moreover, it was unknown which percentage of patients with a (surgically) closed cardiac defect would eventually develop PAH, and what level of PAH leads to symptoms and irreversible changes. Therefore, in chapter 3 we describe the prevalence of PAH in 1877 adults with a closed congenital heart septal defect and examined the risk of developing PAH in this patient group by analysing data from the Euro Heart Survey, a retrospective cohort study with a 5-year follow-up period.

Chapters 4 – 8 depicts on treatment effects of patients with PAH and congenital heart disease. PAH associated with congenital heart disease carries a high risk of mortality and has very limited therapeutic options. Several studies have demonstrated a positive short-term treatment effect of either intravenous prostacyclin, endothelin receptor antagonist or phosphodiesterase-5-inhibitor in this patient group. However, medium-term effects of these treatment strategies are scarce. In chapter 4, we describe the medium-term follow-up of 15 patients treated in a single center with intravenous prostacyclin, an endothelin receptor antagonist, or a phosphodiesterase-5-inhibitor. In chapter 5, the objective of the study was to assess short (4 months) and long-term bosentan effects (≥ 2 years) on functional class and exercise capacity in both adults and children with PAH associated with a systemic-to-pulmonary shunt. Previous studies on therapeutic options in patients with PAH did not involve patients with Down’s syndrome. However, it is suggested that PAH develops earlier in these patients. In chapter 6, we evaluate the safety and tolerability of oral therapy with a dual endothelin receptor antagonist (bosentan) in Down patients with Eisenmenger syndrome by assessing its effects on clinical status and functional capacity. As, in general, the treatment effect of bosentan in patients with PAH due to congenital heart disease is largely unknown, we describe in chapter 7 the treatment effect of bosentan in adult patients with PAH due to congenital heart disease with and without Down syndrome. The aim of this study was to evaluate the longer term treatment effect of bosentan in adult patients with PAH due to congenital heart disease with and without Down syndrome, using exercise capacity and quality of life as primary endpoints.

Treatment with a dual endothelin receptor antagonist has been reported to improve exercise capacity and survival in patients with various forms of PAH, including both PAH due to CHD and to inoperable chronic thromboembolic pulmonary hypertension. Whereas

14


PAH due to congenital heart disease is a chronic condition, PAH due to inoperable chronic thromboembolic pulmonary hypertension is a (sub-)acute condition. Therefore, we hypothesize in chapter 8 that patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension) are more likely to respond positively on treatment compared to patients with life-long pulmonary vessel changes (PAH due to congenital heart disease).

To evaluate the effect of treatment in patients with PAH, the 6-minute walk test is frequently used as primary endpoint. However, in mildly impaired patients obvious improvement in hemodynamics were reported to be accompanied by either no, or minimal improvements in 6-minute walk distance. Therefore, we hypothesize in chapter 9 that the 6-minute walk test does not reflect maximal aerobic capacity in mildly impaired PAH patients.

During treatment of PAH, not all patients show improvement of the 6-minute walk distance. Moreover, predictors for positive treatment effects have not yet been identified. It has been previously shown that in patients with PAH, the duration of right ventricular contraction, measured by echocardiography, is prolonged. In chapter 10 we test whether 1. right ventricular contraction duration at baseline is a predictor of improvement in exercise capacity and 2. if right ventricular contraction duration shortening during treatment is associated with an increase in exercise capacity.

Finally, literature indicates that patients with cyanotic congenital heart disease might be protected against atherosclerosis. Therefore, in chapter 11 we investigate whether a decreased non-invasively measured carotid intima media thickness is accompanied by reduced atherogenic risk factors.

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Reference List 1 MacMahon B, McKeown T, Record RG. The incidence and life expectation of children with congenital

heart disease. Br Heart J 1953;15:121-9.

2 Duffels MG, Engelfriet PM, Berger RM, van Loon RL, Hoendermis E, Vriend JW, van d, V, Bresser P, Mulder BJ. Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry. Int J Cardiol 2007;120:198-204.

3 Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S. Diagnosis and differen-tial assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S-7S.

4 Vongpatanasin W, Brickner ME, Hillis LD, Lange RA. The Eisenmenger syndrome in adults. Ann Intern Med 1998;128:745-55.

5 Bouzas B, Gatzoulis MA. [Pulmonary arterial hypertension in adults with congenital heart disease]. Rev Esp Cardiol 2005;58:465-9.

6 Wood The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J 1958;46:755-62.

7 Engelfriet P.M., Duffels M.G.J., Moller T.Boersma E.Tijssen J.G.P., Thaulow E, Gatzoulis MA, Mulder B.J.M. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007;93:682-7.

8 Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deck-ers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004;25:2243-78.

9 Van der Velde ET, Vriend JW, Mannens MM, Uiterwaal CS, Brand R, Mulder BJ. CONCOR, an initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: rationale, design, and first results. Eur J Epidemiol 2005;20:549-57.

10 Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilen U, Kaemmerer H, Moons P, Meij-boom F, Popelova J, Laforest V, Hirsch R, Daliento L, Thaulow E, Mulder B. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005;26:2325-33.

11 Gidding SS, Stockman JA, III. Erythropoietin in cyanotic heart disease. Am Heart J 1988;116:128-32.

12 Oechslin E Hematological management of the cyanotic adult with congenital heart disease. Int J Cardiol 2004;97 Suppl 1:109-15.

13 Diller GP, Gatzoulis MA. Pulmonary vascular disease in adults with congenital heart disease. Circulation 2007;115:1039-50.

14 Oya H, Nagaya N, Uematsu M, Satoh T, Sakamaki F, Kyotani S, Sato N, Nakanishi N, Miyatake K. Poor prognosis and related factors in adults with Eisenmenger syndrome. Am Heart J 2002;143:739-44.

15 Diller GP, Dimopoulos K, Okonko D, Li W, Babu-Narayan SV, Broberg CS, Johansson B, Bouzas B, Mullen MJ, Poole-Wilson PA, Francis DP, Gatzoulis MA. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation 2005;112:828-35.

16 Niwa K, Perloff JK, Kaplan S, Child JS, Miner PD. Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus, univentricular heart. J Am Coll Cardiol 1999;34:223-32.

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17 Berman EB, Barst RJ. Eisenmenger’s syndrome: current management. Prog Cardiovasc Dis 2002;45:129-38.

18 McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82.

19 Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, Tapson VF, Rubin LJ. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest 2003;124:247-54.

20 Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006;151:851-5.

21 Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associ-ated congenital heart defects. Circulation 1999;99:1858-65.

22 Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Long-term oral bosentan therapy in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2007;93:350-4.

23 Christensen DD, McConnell ME, Book WM, Mahle WT. Initial experience with bosentan therapy in patients with the Eisenmenger syndrome. Am J Cardiol 2004;94:261-3.

24 Fernandes SM, Newburger JW, Lang P, Pearson DD, Feinstein JA, Gauvreau K, Landzberg MJ. Useful-ness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger physiology. Am J Cardiol 2003;91:632-5.

25 Schulze-Neick I, Gilbert N, Ewert R, Witt C, Gruenig E, Enke B, Borst MM, Lange PE, Hoeper MM. Adult patients with congenital heart disease and pulmonary arterial hypertension: first open prospective multicenter study of bosentan therapy. Am Heart J 2005;150:716.

26 Dharmadhikari A, Airoldi F, Tzifos V, Sheiban I, Pathak L, Bansal N. Sildenafil in the treatment of atrial septal defect with moderate to severe pulmonary arterial hypertension. Eur Heart J 2004;25.

27 Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RMF, Lauer A, Chiossi E, Landzberg M, for the Bosentan Randomized Trial of Endothelin Antagonist Therapy-. Bosentan Therapy in Patients With Eisenmenger Syndrome: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study. Circu-lation 2006;114:48-54.

28 Chau EM, Fan KY, Chow WH. Effects of chronic sildenafil in patients with Eisenmenger syndrome versus idiopathic pulmonary arterial hypertension. Int J Cardiol 2007;120:301-305.

29 Duffels M.G.J., Berger R.M.F., Bresser P., de Bruin-Bon H.A.C.M., Hoendermis E., Bouma B.J., Mulder B.J.M. Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity. Neth Heart J 2006;14:165-70.

30 Hoeper MM Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs 2005;65:1337-54.

31 Berger RM Possibilities and impossibilities in the evaluation of pulmonary vascular disease in congenital heart defects. Eur Heart J 2000;21:17-27.

32 Bando K, Turrentine MW, Sharp TG, Sekine Y, Aufiero TX, Sun K, Sekine E, Brown JW. Pulmonary hypertension after operations for congenital heart disease: analysis of risk factors and management. J Thorac Cardiovasc Surg 1996;112:1600-7.

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22Chapter 2

Pulmonary arterial hypertension in congenital heart disease: An epidemiologic perspective from a Dutch registry

Mariëlle GJ Duffels, Peter M Engelfriet, Rolf MF Berger, Rosa LE van Loon, Elke S Hoendermis,

Joris WJ Vriend, Enno T van der Velde, Paul Bresser, Barbara JM Mulder

Int J Cardiol 2007; 120:198-204


AbstractBackground: Pulmonary arterial hypertension (PAH) associated with congenital heart disease is usually the result of a large systemic-to-pulmonary shunt, and often leads to right ventricular failure and early death. The purpose of this study was to determine the prevalence of PAH among adult patients included in a national registry of congenital heart disease and to assess the relation between patient characteristics and PAH.

Methods: Patients with PAH associated with a septal defect were identified from the registry. Gender, age, underlying diagnosis, previous closure, age at repair and NYHA classification were recorded. PAH was defined as a systolic pulmonary arterial pressure (sPAP) greater than 40 mmHg, estimated by means of echocardiographical evaluation.

Results: The prevalence of PAH among all 5970 registered adult patients with congenital heart disease was 4.2%. Of 1824 patients with a septal defect in the registry, 112 patients (6.1%) had PAH. Median age of these patients was 38 years (range 18-81 years) and 40% were male. Of these patients, 58% had the Eisenmenger syndrome. Among the patients with a previously closed septal defect, 30 had PAH (3%). Ventricular septal defect (VSD) was the most frequent underlying defect (42%) among patients with PAH and a septal defect. Female sex (Odds ratio=1.5, p=0.001) and sPAP (Odds ratio=0.04, p<0.001) were independently associated with a decreased functional class.

Conclusion: PAH is common in adult patients with congenital heart disease. In our registry the prevalence of PAH in septal defects is around 6%. More than half of these patients have the Eisenmenger syndrome, which accounts for 1% of the total population in the CONCOR registry. Whether the prevalence of PAH will decrease in the future as a result of early detection and intervention remains to be awaited.

20


IntroductionPulmonary arterial hypertension (PAH) may lead to a decreased functional capacity, and right ventricular failure, and is often associated with early death.1 The prevalence of PAH in patients with congenital heart disease is not known. It has been suggested that 10% of all adult patients with congenital heart disease sooner or later develop PAH.2, 3 In the context of congenital heart disease, PAH may develop as a consequence of a systemic-to-pulmonary shunt. Due to systemic-to-pulmonary shunting, pulmonary blood flow increases. This leads to increased pressure in the pulmonary arteries, endothelial dysfunction and an increased vascular resistance. These changes may ultimately lead to a reversal of the systemic-to-pulmonary shunt accompanied by cyanosis,4 the so-called Eisenmenger syndrome. Eisenmenger syndrome is at the severe end of the spectrum of PAH and involves probably about 1-2% of patients with congenital heart disease.3

Once the Eisenmenger syndrome exists, repair of the underlying defect is contraindicated. The right ventricle will be unable to generate enough pressure to overcome the high pulmonary vascular resistance and decompensate. Surgical correction of the congenital heart defect, during childhood, before the characteristic changes in the pulmonary arteries have started to appear, will mostly prevent the development of PAH.5-7

A few studies have been devoted to the clinical course of the Eisenmenger syndrome, but little is known about the prevalence and clinical impact of PAH among patients with congenital heart defects. Various congenital heart defects may lead to PAH, such as univentricular heart, truncus arteriosus, patent ductus arteriosus and septal defects, but PAH may also develop as a result of surgical shunts (Potts, Waterston, Blalock-Taussig). Although PAH may occur in the context of a wide range of different defects, by far the largest proportion of patients with PAH have a septal defect as underlying defect. For that reason, in this study we focused in particular on ventricular septal defect (VSD), primum or secundum atrial septal defect (ASD I or ASD II, respectively) or complete atrioventricular septal defect (AVSD). As early surgery of the defect will mostly prevent the development of PAH, it is especially important to be informed on the risk of PAH in these patients. What is the prevalence of PAH in this category of patients, and what are the clinical characteristics of adult patients with PAH? To answer these questions, we analyzed data from the CONCOR (CONgenital COR vitia) registry, a nationwide registry of adult patients with congenital heart defects in the Netherlands. This registry was set up as a basis for studying the epidemiology of congenital heart defects and includes patients with structural congenital heart defects or Marfan syndrome. In the registry are not included, patients with cardiomyopathies (i.e. arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, dilated cardiomyopathy) or inherited diseases leading to genetically determined cardiac arrhythmias and sudden death (i.e. long QT syndrome, Brugada syndrome).8 Consistent input of data by dedicated nurses travelling along the participating hospitals may guarantee a rather high consistency of data input and a rather low amount of missing data.

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ter 2Pulm

onary arterial hypertension in cong

enital heart disease


Patients and methods

Patient population

In November 2005, the CONCOR registry contained diagnoses and clinical events of 5970 adult patients with congenital heart disease from 86 tertiary and regional hospitals.8 Our assessment of the prevalence of PAH consisted of two parts. In a first, global, analysis, we estimated the prevalence of PAH among all patients at risk for developing PAH. Thus, we defined a total “population at risk”, which included all patients in the registry who had as primary diagnosis a defect that may lead to PAH, i.e. one of the following defects: ASD I or II, VSD, AVSD (septal defects), patent ductus arteriosus, double inlet left ventricle, double outlet right ventricle, ductus arteriosus, or a surgical shunt (Potts, Waterston, Blalock-Taussig) in combination with another defect. We excluded defects that may lead to pulmonary hypertension in which the pathophysiology is congestion in the venous part of the pulmonary circulation. Next, for each of these patients we noted whether or not their record in the registry mentioned the diagnosis of PAH.8 The diagnosis of PAH is entered in the registry when mentioned in the patients record by the treating cardiologist. We then determined the prevalence of PAH by dividing the number of cases with PAH by the population at risk (times 100).

In a second assessment, for reasons explained above, we focused on the patients with a septal defect. For these patients, we performed a more extensive review of the medical records. The reasons for going back to the patient files were two-fold. Firstly, we further evaluated cases with missing values in the registry. When values of measurements of sPAP could still not be found in this additional search, we assumed that the patient did not have PAH. Secondly, we wanted to obtain all available sPAP values to be able to perform analyses using quantitative sPAP values. sPAP was assessed on the basis of echocardiographic evaluation (tricuspid regurgitation jet velocity measurements) because invasive data were generally not available. The latest recorded PAP value was used. In this study, PAH was defined as a sPAP above 40 mmHg.9, 10 Patients with a documented right ventricular outflow tract obstruction, or left sided cardiac valvular disease were excluded, because in the first case the right ventricular systolic pressure does not represent pressure in the pulmonary artery, and in the second case, left sided cardiac valvular disease may contribute to pulmonary venous hypertension.

Patients with a septal defect were classified into 2 groups: patients with the Eisenmenger syndrome and patients without Eisenmenger syndrome but with PAH (the “non-Eisenmenger” group). For each patient, apart from sPAP, the following data were collected: gender, age, underlying diagnosis, whether or not the underlying defect had been closed, age at repair and NYHA classification.

Statistical analysis

Continuous data were presented as mean with standard deviation when distributed normally and as median with range otherwise. Discrete data were given as counts, or as percentages.

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Differences between groups were assessed using the chi-square, T-test or Mann-Whitney U-test: Pearson correlation coefficients were calculated to investigate the relationship of sPAP with NYHA class. Ordinal multivariate regression analysis was used to identify independent predictors for NYHA class. Logistic regression analysis was used to identify independent predictors for PAH. For each of the analyses, p< 0.05 was considered statistically significant.

Results

Population

Of the total population included in the CONCOR registry (5970 patients) from 86 hospitals, the population at risk existed of 2389 patients (see table 1), having one of the defects mentioned in the methods section. Of those, 248 (10%) had PAH. In total, the prevalence of PAH among congenital heart disease patients was 4.2%. Further, 1824 patients (31%) were identified as having a septal defect; in 899 of these patients the septal defect had been closed. Of the 1824 patients with a septal defect, 112 (6.1%) patients had PAH.

Table 1. Prevalence of pulmonary arterial hypertension in the population at risk

Defect N PAH %

Atrial septal defect II 717 55 8

Atrial septal defect I 201 15 7

Ventricular septal defect 799 85 11

Atrioventricular septal defect 95 39 41

Patent ductus arteriosus 71 2 3

Truncus arteriosus 17 1 6

Aortopulmonary window 2 2 100

Double inlet left ventricle 28 2 7

Double outlet right ventricle 47 8 17

Univentricular heart 55 6 11

Other + Surgical shunt 357 33 9

Total 2389 248 10

Baseline characteristics of patients with a septal defect and PAH are summarized in table 2. Of the 112 patients with PAH, 65 (58%) patients had the Eisenmenger syndrome. This accounts for 1.1% of all patients (5970) registered in the CONCOR registry. Mean sPAP in patients with Eisenmenger syndrome was 89 mmHg, and in non-Eisenmenger patients 53 mmHg. Among the patients with a septal defect, the proportion of patients treated at a tertiary referral hospital was different between the patients with and without PAH: 85% of patients with PAH versus 69% of patients without PAH (p<0.001).

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Underlying defect

VSD was the most frequent underlying defect among all patients with PAH (42%) in the septal defect group. Most of the VSD’s (n=39; 83%) had not been closed. Of all patients with a VSD and PAH, 31 (79%) patients had Eisenmenger syndrome. Of the eight (21%) patients without Eisenmenger syndrome, one had refused operation, four had borderline PAH, one was on the waiting list for VSD closure and in two cases operative risk was deemed too high (co-morbidity). Mean sPAP in these non-closed VSD patients without Eisenmenger syndrome was not significantly higher compared to patients with a closed VSD (54±13 mmHg vs. 59±17 mmHg, respectively; p=0.50).

In the non-Eisenmenger patients with PAH, ASD II was the most frequent underlying diagnosis (n=20, 38%). Most of the ASD II’s had not been closed (n=16; 57%). Of all patients with an ASD II and PAH, eight (29%) patients had Eisenmenger syndrome. Of the eight (29%) patients without Eisenmenger syndrome, one had refused operation, five were on the waiting list for ASD closure, in one case risk of closure was deemed too high (co-morbidity) and in one patient it was unknown why the defect had not been closed. It should be noted, that 12 of the 426 patients (3%) with a closed ASD II developed PAH.

The proportions of patients with PAH is shown, for each septal defect, in figure 1. The prevalence of PAH was 11 % among 799 patients with VSD, 8% among 717 patients with ASD II, 7% among 201 patients with ASD I, and 41 % among 95 patients with AVSD. So,

Table 2. Baseline characteristics of patients with a septal defect and PAH

Eisenmenger syndrome(n= 65)

Non- Eisenmenger Total(n= 112) Not closed

(n= 17)Closed defect

(n= 30)

Male 40% 41% 40% 40%

Median age, years (range) 36 (18-70) 57 (23-80) 37 (21-81) 38 (18-81)

Underlying diagnosis (%)

VSD 31 (48) 8 (47) 8 (27) 47 (42)

ASD II 8 (12) 8 (47) 12 (40) 28 (25)

ASD I 3 (5) 1 (6) 5 (17) 9 (8)

AVSD 23 (35) 0 (0) 5 (17) 28 (25)

Mean PAP, mmHg (± SD) 89 (± 21) 58 (± 19) 49 (± 12) 71 (± 26)

NYHA classification (%)

I 6 (12) 4 (29) 13 (48) 23 (25)

II 15 (29) 8 (57) 8 (30) 31 (33)

III 28 (54) 0 (0) 6 (22) 34 (37)

IV 3 (6) 2 (14) 0 (0) 5 (5)

VSD = ventricular septal defect, ASD II = secundum atrial septal defect, ASD I = primum atrial septal defect, AVSD = atrioventricular septal defect, PAP= pulmonary arterial hypertension.

24


PAH was most prevalent in patients with AVSD. Nineteen (70%) of these AVSD patients had Down syndrome. Of these, 17 had Eisenmenger syndrome and 2 had closed defects.

Age distribution

In figure 2a, the age distribution of all patients (1824) with a septal defect in the CONCOR registry is shown. The majority of patients with a septal defect were between 20 and 40 years of age. This is also shown in figure 2b for the PAH group. Eisenmenger patients and non-Eisenmenger patients were equally distributed over all age groups until the age of 70 (figure 2b). Patients with Eisenmenger syndrome were younger compared to non-Eisenmenger patients with an open defect and PAH (respectively 36 vs. 57 years, p<0.01) (table 2). The oldest patient among the Eisenmenger patients was 69 years old (ASD II) compared with a patient aged 81 years in the non-Eisenmenger group (ASD I). In figure 2c, the age distribution per septal defect of the patients with PAH is shown. No difference was found in age distribution among the septal defects and among the three subgroups Eisenmenger syndrome, non- Eisenmenger with an unclosed defect and PAH with a closed defect.

Gender distribution

In the CONCOR registry, among the patients with a septal defect there were relatively more females (59%) compared to patients without a septal defect (45%; p<0.001). This is mostly due to the large proportion of ASD II (46%) among patients with a septal defect of whom 64% were female. The prevalence of PAH among male and female patients with a septal

0

200

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VSDASD

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IAVSD

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Patients with pulmonary arterial hypertensionConcor patients with a septal defect

Figure 1. Total number of patients (n=1824) per type of septal defect in the CONCOR registry. PAH: pulmonary arterial hypertension; VSD: ventricular septal defect; ASD II: atrial septal defect secundum; ASD I: atrial septal defect primum; AVSD: complete atrioventricular septal defect.

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Figure 2A,B, C. Panel A shows the age distribution of 1824 patients with one of the following septal defects: atrial septal defect type I or II, ventricular septal defect, or complete atrioventricular septal defect. Panel B shows the age distribution of the patients (n=112) with pulmonary arterial hypertension among the patients with a septal defect (see figure 2A). “Non-Eisenmenger” refers to patients without Eisenmenger syndrome but with pulmonary arterial hypertension. Panel C shows the age distribution per underlying septal defect of the patients (n=112) with pulmonary arterial hypertension.

0

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26


defect was similar, both overall and per defect (7.8 vs. 7.6%, p=n.s). As a consequence, there were more females than males with PAH. Apart from ASD II, gender distribution among PAH patients was similar in the different underlying diagnoses (figure 3). Similarly, no difference was found in the gender distribution between Eisenmenger and non-Eisenmenger patients (60 and 59%, resp.).

Figure 3. Percentage of females among the patients with pulmonary arterial hypertension and a septal defect. The numbers in the bars represent the absolute numbers of females. VSD: ventricular septal defect; ASD II: atrial septal defect secundum; ASD I: atrial septal defect primum; AVSD: complete atrioventricular septal defect.

0 10 20 30 40 50 60 70 80 90 100

AVSD

ASD I

ASD II

VSD

Total

Female (%)

Closure of defect

In patients with an open septal defect (925), 82 had PAH, of whom 65 had Eisenmenger syndrome. In patients with PAH and an open septal defect, mean sPAP tended to be higher compared to patients with a closed septal defect and PAH (58 vs. 49 mmHg, respectively p=0.06). Among 899 patients with a closed septal defect, 30 (3%) patients had developed PAH in spite of previous closure. The prevalence of PAH was 4 % among patients with a closed VSD and 3 % among patients with a closed ASD II (p=0.6).

In ASD II, age at repair was independently associated with the development of PAH (Odds=1.1, p=0.01), after correction for age and gender. In the other septal defects this association did not reach statistical significance.. In patients with VSD, median age at repair was comparable in patients with PAH (6.3 (3.9-11) years) and without PAH (7.0 (0-62) years; p=n.s.). Median age at repair, among patients with PAH, was significantly different between patients with VSD and ASD II (7 (4-11) vs. 50 (1-76) years; p=0.03)). The difference between mean sPAP among patients with either a closed VSD or ASD II was not significant (59±17 vs. 46±5, p=0.5 respectively).

NYHA classification

The majority of the Eisenmenger patients were in NYHA class III (54%), whereas most non-Eisenmenger patients with PAH (81%) were in class I or II (p<0.001). Figure 4 shows the

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Female patients (n=64)

0%

5%

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15%

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25%

30%

35%

40%

45%

NYHA I NYHA II NYHA III NYHA IV

Perc

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Male patients (n=39)

0%

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NYHA I NYHA II NYHA III NYHA IV

Perc

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Figure 4. Relation between systolic pulmonary arterial pressure and NYHA functional class. The horizontal bars represent mean systolic pulmonary arterial pressure for each class.

Figure 5A, B. Panel A shows the percentage of male patients with pulmonary arterial hypertension per NYHA classification. Panel B shows the percentage of female patients with pulmonary arterial hypertension per NYHA classification. In both panels, Bars represented percentages. The whole bars sum to 100%. Subdivisions of the bars represent the proportions taken up by the individual defects within each NYHA class.

28


relationship between sPAP and NYHA class. The increase of sPAP correlates with decreasing functional capacity (r=0.49, p<0.001). Figure 5, panels A. and B. shows a significant difference in functional class according to gender: relatively more females than males were symptomatic; 41% of the males were in NYHA class I compared to 13% of the females. Most females (82%) were in NYHA functional class II and III. Mean sPAP was not different between males and females (72 vs. 71 mmHg, p=0.8). Multivariate analyses adjusting for age showed that female sex (Odds ratio=1.5, p=0.001) and increased sPAP (Odds ratio=0.04, p<0.001) were both independently associated with a worse NYHA functional class.

DiscussionOur data show that the prevalence of PAH among patients with a septal defect is at least 6.1% among adult patients included in the CONCOR registry. The estimated prevalence of PAH among all patients included in the CONCOR registry as a whole is at least 4.2%. One percent of all patients (5970) registered in the CONCOR registry had the Eisenmenger syndrome. VSD was the most common underlying diagnosis among patients with PAH in the septal defect group. Female sex and increased sPAP were both independently associated with worse NYHA functional class.

Prevalence

To our knowledge, this is the first study reporting on the prevalence of PAH and Eisenmenger syndrome among adult patients with congenital heart disease. Our sample consisted of patients believed to be representative of the general population of adult patients with congenital heart disease. Although, at present, patients attending tertiary referral hospitals are still overrepresented, it is the aim of the CONCOR registry to detect all patients with congenital heart disease in the Netherlands. As always, there are disadvantages in using data collected as part of a registry. Moreover, this registry was not specifically designed to detect PAH. In particular, for many patients values of measurements of sPAP were lacking. When such patients were not registered as having PAH, we assumed that they, indeed, did not have PAH and counted them in the denominator but not in the numerator. It is thus likely that our estimate of 4.2% is an underestimation of the true prevalence. Prevalence of PAH between 5-10% seems realistic.2, 3 Unfortunately, PAH may proceed gradually without causing overt symptoms and thus may remain undetected for a long period of time.

PAH may occur in the context of a wide range of different defects. Among such defects, by far the largest group of patients with congenital heart disease at risk for developing PAH consists of patients with septal defects. It is, therefore, especially important to be informed on the risk of PAH in these patients. Furthermore, in such patients the progress to severe PAH and Eisenmenger syndrome, is considered to be preventable. However, our data shows that 3% of the patients with a previously closed septal defect had developed PAH. So, closure of

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the septal defect apparently did not prevent the development of PAH. In retrospect, some of these patients might have been operated too late. In ASD II, age at repair was independently associated with the development of PAH. In the other septal defects this association did not reach statistical significance due to the small numbers of patients.

It is possible that the prevalence of PAH will decrease in the future as a result of improved early detection and timely intervention. In fact, our population reflects the treatment strategies of 20 years and more ago, since then management has changed in a few aspects, Down syndrome, for example is no longer considered a contraindication for operation. It can be expected that operation will contribute to the prevention of Eisenmenger syndrome in these patients. Further, an unclosed significant VSD may lead to substantial pathology later in life, in particular PAH and left ventricle overload.11 Development of PAH has been reported to be rare after closure of a VSD in the first 2 years of life.7 Therefore, with detection and closure of VSD at younger age, one might expect that future decrease in the prevalence of PAH is likely. However, sPAP increases with age in healthy adults.9 Systolic PAP > 40 mmHg is present in 6% of otherwise normal individuals older than 50 years, and 5% in obese patients with a BMI > 30 kg/m2.9, 12 More research is needed on the course of PAH after (non-) closure of the defect, to estimate the prevalence of PAH in the future.

Age, gender and underlying diagnosis

Patients with Eisenmenger syndrome in this study were relatively younger than non-Eisen-menger patients with an open defect and PAH. This is partly due to a decreased life expectancy of patients with Eisenmenger syndrome. In addition, among the patients with an open defect a greater proportion had an ASD II as an underlying defect. It is known that these patients often remain asymptomatic for a long period, and only come to medical attention when they develop symptoms later in life.

It has been suggested that there is a predisposition to PAH in females.13 On the other hand, Wood14 described that males and females develop PAH at a similar rate. In our data set, we indeed found a larger proportion of females. However, the prevalence of PAH among males and females with a septal defect was similar. The larger proportion of females is a result of the gender distribution of patients with a septal defect in the CONCOR registry.13,

15 In particular, it is known also from other studies that among patients with secundum ASD’s females predominate. 15-18

Overall, VSD was the most common underlying defect among patients with PAH in the septal defect group. This is consistent with previous studies, in which VSD was found to be the most common congenital heart defect among patients with PAH, accounting for 33-50%.2, 13,

19 Of the unclosed VSD’s, 79% had already developed Eisenmenger syndrome. It seems that, once patients with VSD develop PAH it soon leads to Eisenmenger syndrome. It is further remarkable that of patients with a previously closed ASD II, 3% had PAH. Apparently, closure of an ASD II is not always followed by reversal of the PAH. This could be due to the fact that

30


these secundum ASDs have been closed too late.11 On the other hand, individual genetic predisposition could be a risk factor for the development of advanced PAH.20

Functional capacity

The majority of patients with PAH had severe functional limitations. Female sex and increased sPAP were independently associated with a worse NYHA class. Mean sPAP was not different between males and females in our study. Possibly, this worse NYHA class in females exists as a result of influences of specific hormonal factors.13 It is as expected that functional class was worst in the Eisenmenger patients.21 This could be due to higher sPAP.

Study limitations

This was a retrospective analysis of data collected as part of a national registry. As a consequence, due to lacking data, some of our estimates represent lower limits rather than estimates of true prevalence. However, the consistent input of data by two dedicated nurses travelling along the 86 participating hospitals may guarantee a rather high consistency of data input and a rather low amount of missing data. As for the septal defects, medical records were reviewed, which allows an even higher accuracy for this dataset. PAH is commonly defined as a mean PAP above 25 mmHg in rest or above 30 mmHg during exercise, measured by right heart catheterization.9, 12 However, data from right heart catheterization is seldom available in this registry. Therefore, in this study we used echo measurements. The criterion of PAH, detected by echocardiography, is not clearly defined, PAH is suggested when an echocardiography-derived estimate of sPAP exceeds 40 mmHg at rest.10

ConclusionOur study reports on the prevalence and clinical characteristics of patients with PAH included in CONCOR, a national registry of adult patients with congenital heart disease in The Netherlands. The prevalence of PAH among all patients in CONCOR is at least 4.2%. Among patients with a septal defect the prevalence of PAH is at least 6%. Fifty-eight percent of these patients presented with the Eisenmenger syndrome which accounts for 1% of the total population in the CONCOR registry. Among the closed septal defects 3% had still developed PAH. Female gender and increased sPAP were independently associated with decreased functional class. So far, it is uncertain whether the prevalence of PAH will decrease in the future as a result of systematic and early intervention. Periodic checkup of predisposed patients may detect progression and allow early therapy.

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Reference List 1 Daliento L, Somerville J, Presbitero P, Menti L, Brach-Prever S, Rizzoli G, Stone S. Eisenmenger

syndrome. Factors relating to deterioration and death. Eur Heart J 1998;19:1845-55.

2 Vongpatanasin W, Brickner ME, Hillis LD, Lange RA. The Eisenmenger syndrome in adults. Ann Intern Med 1998;128:745-55.


4 Granton JT, Rabinovitch M. Pulmonary arterial hypertension in congenital heart disease. Cardiol Clin 2002;20:441-57, vii.



7 McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G. Progno-sis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:78S-92S.


9 McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmo-nary artery systolic pressure among echocardiographically normal subjects. Circulation 2001;104:2797-802.

10 Rubin LJ, Badesch DB. Evaluation and management of the patient with pulmonary arterial hyperten-sion. Ann Intern Med 2005;143:282-92.

11 Engelfriet P, Tijssen J, Kaemmerer H, Gatzoulis MA, Boersma E, Oechslin E, Thaulow E, Popelova J, Moons P, Meijboom F, Daliento L, Hirsch R, Laforest V, Thilen U, Mulder B. Adherence to guidelines in the clinical care for adults with congenital heart disease: the Euro Heart Survey on adult congenital heart disease. Eur Heart J 2006;27:737-45.


13 Somerville J The Denolin Lecture: The woman with congenital heart disease. Eur Heart J 1998;19:1766-75.

14 Wood The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J 1958;46:755-62.

15 Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilen U, Kaemmerer H, Moons P, Meij-boom F, Popelova J, Laforest V, Hirsch R, Daliento L, Thaulow E, Mulder B. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period: The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005;26:2325-33.

16 Vogel M, Berger F, Kramer A, exi-Meshkishvili V, Lange PE. Incidence of secondary pulmonary hyper-tension in adults with atrial septal or sinus venosus defects. Heart 1999;82:30-3.

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17 Steele PM, Fuster V, Cohen M, Ritter DG, McGoon DC. Isolated atrial septal defect with pulmonary vascular obstructive disease--long-term follow-up and prediction of outcome after surgical correction. Circulation 1987;76:1037-42.

18 Campbell M Natural history of atrial septal defect. Br Heart J 1970;32:820-6.

19 Saha A, Balakrishnan KG, Jaiswal PK, Venkitachalam CG, Tharakan J, Titus T, Kutty R. Prognosis for patients with Eisenmenger syndrome of various aetiology. Int J Cardiol 1994;45:199-207.

20 Roberts KE, McElroy JJ, Wong WP, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 2004;24:371-4.


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33Chapter 3

Pulmonary arterial hypertension in adults born with a heart septal defect: The Euro Heart Survey on adult congenital heart disease

Peter M Engelfriet, Mariëlle GJ Duffels, Thomas Møller, Eric Boersma, Jan GP Tijssen, Erik

Thaulow, Michael A Gatzoulis, Barbara JM Mulder

Heart 2007; 93:682-687


AbstractAim: To investigate the role of pulmonary arterial hypertension (PAH) in adult patients born with a cardiac septal defect, by assessing its prevalence and its relation with patient characteristics and outcome.

Methods and results: From the database of the Euro Heart Survey on adult congenital heart disease (a retrospective cohort study with a 5-year follow-up), the relevant data on all 1877 patients with an atrial septal defect (ASD), a ventricular septal defect (VSD), or a cyanotic defect were analysed. Most patients (83%) attended a specialised centre. There were 896 patients with an ASD (377 closed, 504 open without, and 15 with Eisenmenger’s syndrome), 710 with a VSD (275, 352, 83, respectively), 133 with Eisenmenger’s syndrome owing to another defect and 138 remaining patients with cyanosis. PAH was present in 531 (28%) patients, or in 34% of patients with an open ASD and 28% of patients with an open VSD, and 12% and 13% of patients with a closed defect, respectively. Mortality was highest in patients with Eisenmenger’s syndrome (20.6%). In case of an open defect, PAH entailed an eightfold increased probability of functional limitations (New York Heart Association class > 1), with a further sixfold increase when Eisenmenger’s syndrome was present. Also, in patients with persisting PAH despite defect closure, functional limitations were more common. In patients with ASD, the prevalence of right ventricular dysfunction increased with systolic pulmonary artery pressure (OR = 1.073 per mm Hg; p < 0.001). Major bleeding events were more prevalent in patients with cyanosis with than without Eisenmenger’s syndrome (17% versus 3%; p < 0.001).

Conclusion: In this selected population of adults with congenital heart disease, PAH was common and predisposed to more symptoms and further clinical deterioration, even among patients with previous defect closure and patients who had not developed Eisenmenger’s physiology.

36


IntroductionIn heart defects with incomplete physical separation of the systemic and pulmonary circulation, such as septal defect, shunting of blood from left to right may lead to increased flow and pressure in the pulmonary circulation. When this, in turn, induces irreversible changes of the medium-sized and small arteries, the pressure in the pulmonary artery may reach the height of systemic pressures, with consequent reversal of the shunt and cyanosis, a condition known as Eisenmenger’s syndrome. Prevention of this sequence of events is an important target in the management of septal defects, and may, in particular, motivate closure of the defect. However, the clinical course of patients with septal defects is variable. In particular, it is not known how frequently pulmonary arterial hypertension (PAH) develops since closure of defects has taken place, and which levels of PAH lead to symptoms and irreversible changes.

The recently completed Euro Heart Survey on congenital heart disease in adults included a considerable number of patients with septal defects. We used this relatively large multicentre database to examine the potential role of PAH in adults born with a heart septal defect, including patients with Eisenmenger’s syndrome.

MethodsAll patients were selected from the database of the Euro Heart Survey on adult congenital heart disease who had a type II atrial septal defect (ASD) as the primary diagnosis, or a ventricular septal defect (VSD), Eisenmenger’s syndrome, or another cyanotic defect. The methods that were used to collect the data for the Euro Heart Survey have been described previously.1, 2 Briefly, consecutive patients with one of eight congenital cardiac defects visiting an outpatient clinic of one of the participating centres in 1998 were identified, and their clinical course was documented in retrospect until April 2004. Data on medical history, results of diagnostic procedures and interventions were transcribed from patient records into an electronic case record file. Participating centres included both specialised (tertiary referral) centres and non-specialised centres. A specialised centre was defined as a centre fulfilling the following three criteria: (1) paediatric cardiology or congenital cardiac surgery available; (2) at least one cardiologist dedicated to adult congenital heart disease; (3) a minimum of 200 congenital outpatient visits per year.

For this analysis, the following data collected in the survey for the above categories of patients were used: general patient information (age and sex), medical history (arrhythmias and major bleeding events in patients with cyanosis), thromboembolic events and interventions, in particular, closure of the defect. Major bleeding evens were defined as bleeding requiring hospital admission and were further categorised as “haemoptysis”, “intracranial haemorrhage” or “other”. Baseline clinical characteristics were: systolic pulmonary artery pressure (sPAP), ventricular function, and New York Heart Association (NYHA) functional class. Changes during follow-up were: death, interventions pertaining to the septal defect and change in functional status (NYHA class).

37

Chap

ter 3The p

revalence of pulm

onary arterial hypertension in The Euro H

eart Survey


Subgroups of patients

Patients were divided into subgroups for the purpose of analysis according to type and closure status (open or closed) of the defect, presence or absence of cyanosis, and presence or absence of Eisenmenger’s physiology. Patients with Eisenmenger’s patients were further distinguished according to underlying defect.

Definition of pulmonary arterial hypertension

PAH is usually defined as a sPAP of > 25 mm Hg, when measured invasively, or > 35 mm Hg when estimated echocardiographically on the basis of measurement of the velocity of the tricuspid regurgitation jet.3, 4 For the purposes of this study, PAH was assumed to exist when a value of ≥ 40 mm Hg had been entered in the patient record, or when sPAP was qualified as “abnormal”.


Categorical baseline characteristics were expressed as percentages and compared among the relevant groups with Pearson’s X2 test. Continuous variables were expressed as mean (SD) when normally distributed and compared with the two-tailed t test for independent samples, or, when not normally distributed, as medians (1st -3rd quartiles) and compared with the Mann-Whitney U test. Normality was assessed with the Kolmogorov-Smirnov test. Two-sided p values of < 0.05 were considered as significant.

The prevalence of PAH and the relationship with age and sex

For each subgroup, the prevalence of PAH was expressed as a percentage calculated from the number of patients fulfilling the criteria for PAH at baseline, and the total number of patients included in that subgroup. To explore the relationship with age and sex, age and sex distribution were compared between patients with and without PAH. The association of prevalence with age was further assessed using a multivariate analysis taking the presence of PAH as the dependent variable, and with the following independent variables included in the model: age, type of defect (VSD or ASD), closure status (defect closed or open at inclusion in the study) and sex.

PAH, sPAP and NYHA functional status

In a first exploratory analysis, values for sPAP were compared between patients grouped into three categories according to their baseline functional status: NYHA class I, NYHA class II, or NYHA class III/IV. This was done separately for patients with an open ASD and those with an open VSD, in both cases excluding the patients with Eisenmenger’s physiology. The association between sPAP and NYHA class was analysed with the Kruskal-Wallis test, the Mann-Whitney U test for pairwise comparisons, and the Jonckheere-Terpstra test for a trend.

38


This exploratory analysis was followed by logistic regression to describe the relation between PAH and functional status adjusting for potential confounders, with the presence of symptoms (NYHA class > I) as the dependent variable. Independent variables included in the model were PAH status, presence or absence of Eisenmenger’s physiology, type of defect, age and sex.

The association between PAH and outcome

Standard techniques of survival analysis were employed to investigate the relationship between PAH and mortality. Kaplan-Meier curves were generated comparing the subgroups. The following subgroups were compared with the log rank test: (1) among patients with cyanosis those with and those without PAH; (2) among patients with cyanosis, those with Eisenmenger’s syndrome and those with cyanotic defect; (3) among patients with Eisenmenger’s syndrome those with different underlying defects. Patients with open defects at baseline whose defect was closed during follow-up were considered censored at the date of closure.

Right ventricular function and pulmonary artery pressure

Right ventricular function was evaluated according to three categories: good (ejection fraction > 50%, or qualified as “good” in the patient record), moderate (30-50%, or “moderate”) or poor (< 30% or “poor”). Right ventricular dysfunction was then defined as moderate or poor right ventricular function. Presence of right ventricular dysfunction was taken as the dependent variable in a logistic regression analysis to investigate the relationship between sPAP and ventricular function.

Cyanosis versus PAH in the Eisenmenger syndrome

To differentiate the effects of cyanosis from those that can be ascribed to PAH itself, baseline characteristics were compared between the patients with cyanosis with Eisenmenger’s syndrome and those without. To further investigate the significance of one variable that was identified as distinguishing between the groups (a history of major bleeding events), logistic regression was used in order to adjust for the degree of cyanosis (resting oxygen saturation) and general potential confounders (age and sex).

All statistical analyses were performed using the SPSS package, V.12.01.

ResultsThe database contained data on 1877 patients who had one of the relevant defects. These patients were included in a total of 76 centres; 1553 (83%) of the patients were treated at a specialised centre. Table 1 shows the distribution of these patients in the various subgroups, and displays their baseline characteristics. Patients with cyanosis without Eisenmenger’s syndrome had the following underlying defects: pulmonary atresia (n=36), abnormal pulmonary venous

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drainage (n=5), double inlet left ventricle (n=23), truncus arteriosus (n=4), transposition of the great arteries (n=10), Ebstein abnormality (n=6) and complex/ other/ unspecified (n=54).

Baseline patient characteristics

In all groups, there were more females, especially among patients with ASD and in the group “Eis other” (Eisenmenger’s syndrome with an underlying defect other than a simple ASD or VSD). Patients with VSD were younger than patients with ASD, and patients with Eisenmenger’s syndrome were older than those without.

Prevalence of PAH

A total of 531 patients (28% of all patients) were identified as having PAH. Table 1 displays the percentages of patients with PAH. Among all patients with open defects, including the patients with Eisenmenger’s syndrome, 34% (179/519) of patients with ASD and 28% (122/435) of patients with VSD had PAH; in patients with a closed defect, the corresponding figures were 12% (45/377) and 13% (35/275), respectively.

The relation with age and gender

In patients with an ASD, median age was 15 years higher in patients with PAH compared to those without (51 years versus 36 years; p < 0.001). In patients with a VSD, this difference was 30 years versus 26 years (p = 0.001). In line with these age differences, the prevalence of PAH was significantly higher among patients aged ≥ 40 years: among patients with an open ASD (including Eisenmenger’s syndrome), 49.4% versus 18.9% (p < 0.001), and among those with an open VSD, 40.2% versus 25.0% (p=0.007).

Multivariate analysis, adjusting for type of defect, closure status, and sex, showed that the probability of PAH increased with a factor of 1.041 (p < 0.001) for each extra year of age.

Table 1: Baseline characteristics per subgroup of a total number of 1877 patients

Closed ASD

Open ASD

Closed VSD

Open VSD

Cyan. Non-Eis Eis other

Eisenmenger’s syndrome Eisenmenger’s syndrome

No Yes No Yes

N 377 504 15 275 352 83 138 133

Age (median) 38 40 44 27 27 30 28 28

Females (%) 65% 68% 80% 53% 53% 55% 59% 68%

PAH, N (%) 45 (12%) 164 (33%) 15 (100%) 35 (13%) 39 (11%) 83 (100%) 17 (12%) 133 (100%)

median PAP (I.Q. range) 30 (26-38) 38 (30-50) 110 (92-126) 30 (25-40) 31 (25-38) 106 (96-119) 22 (17-30) 104 (90-120)

ASD=Atrial Septal Defect; VSD=Ventricular Septal Defect; Cyan Non-Eis=Cyanotic Defect without Eisenmenger Syndrome; Eis other= Eisenmenger Sydrome with an underlying defect other than a simple ASD or VSD; PAH=Pulmonary Arterial Hypertension; I.Q.=interquartile range

40


In none of the subgroups was there a significant relation between sex and the prevalence of PAH.

Association between sPAP, PAH and NYHA functional class

It is shown in figure 1 that among patients who had an open septal defect without Eisenmenger’s physiology, sPAP increased with NYHA class, both in patients with ASD (figure 1A) and in patients with VSD (figure 1B; p < 0.001 for all comparisons).Figure 1. Distribution of systolic pulmonary artery pressure (sPAP) according to New York Heart Association (NYHA) functional class for patients with an open septal defect but without

Table 1: Baseline characteristics per subgroup of a total number of 1877 patients

Closed ASD

Open ASD

Closed VSD

Open VSD

Cyan. Non-Eis Eis other

Eisenmenger’s syndrome Eisenmenger’s syndrome

No Yes No Yes

N 377 504 15 275 352 83 138 133

Age (median) 38 40 44 27 27 30 28 28

Females (%) 65% 68% 80% 53% 53% 55% 59% 68%

PAH, N (%) 45 (12%) 164 (33%) 15 (100%) 35 (13%) 39 (11%) 83 (100%) 17 (12%) 133 (100%)

median PAP (I.Q. range) 30 (26-38) 38 (30-50) 110 (92-126) 30 (25-40) 31 (25-38) 106 (96-119) 22 (17-30) 104 (90-120)

ASD=Atrial Septal Defect; VSD=Ventricular Septal Defect; Cyan Non-Eis=Cyanotic Defect without Eisenmenger Syndrome; Eis other= Eisenmenger Sydrome with an underlying defect other than a simple ASD or VSD; PAH=Pulmonary Arterial Hypertension; I.Q.=interquartile range

P = 0.004

I II III/IVNYHA class

0

20

40

60

80

100

120

PAP

(mm

Hg)

132 430

321 434 118

P < 0.001

P < 0.001

P < 0.001

Test for a trend: P < 0.001

ASD

0

20

40

60

80

100

120

PAP

(mm

Hg)

I II III/IVNYHA class

P < 0.001VSD

Figure 1. The panels show the distribution of systolic pulmonary artery pressure according to New York Heart Association functional class values for patients with an open septal defect but without Eisenmenger physiology. Panel A shows the results for Atrial Septal Defect; Panel B for Ventricular Septal Defect. The thick black lines indicate the median, the boxes the interval between the 25 en 75 percentiles, and the outer lines the extreme values. PAP=Pulmonary Artery Pressure; NYHA=New York Heart Association.

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Eisenmenger’s physiology. (A) the results for atrial septal defect; (B) results for ventricular septal defect (VSD). The thick black lines indicate the median, the boxes the interval between the 25th en 75th percentiles, and the outer lines the extreme values.

Table 2 displays the results of the subsequent logistic regression analysis for patients with an open defect, with or without Eisenmenger’s physiology. After adjustment for age, sex, and type of defect, the presence of PAH was found to entail an almost eightfold increased probability of functional limitations. The presence of Eisenmenger’s syndrome was associated with an additional sixfold increase in probability.

Table 2: Determinants of baseline functional limitations (NYHA class)

Variable Odds Ratio 95% CI P-value

PAH present 7.7 5.1 - 11.8 < 0.001

Eisenmenger present 6.3 2.8 - 14.2 < 0.001

VSD versus ASD 0.37 0.26 - 13.4 < 0.001

age > 40 2.4 1.7 - 3.4 < 0.001

Female sex 1.1 0.79 - 1.5 0.571

The relation between PAH and exercise capacity was also explored in patients with a closed defect. In these patients, after adjustment for age and sex, PAH was associated with a sevenfold increased probability (odds ratio (OR) 7.1, 95% CI 3.5 to 15.1; p < 0.001) in the case of an ASD, and a 12-fold increased probability (OR 11.8, 95% CI 5.1 to 27.5; p < 0.001) in the case of a VSD.

PAH and outcome

Figure 2A, B displays Kaplan-Meier curves. For each of the two defects, there were differences in survival according to subgroup (p < 0.0001), but the significance of this result was largely due to the high mortality in patients with Eisenmenger’s syndrome as compared to the other subgroups. The presence of PAH seemed to be associated with increased mortality more strongly in the group of patients with closed defects. In patients with a closed ASD, (Kaplan-Meier) estimated survival for those with versus those without PAH was 94.8% and 98.4%, respectively (p = 0.036; log rank test, not correcting for multiple testing). In patients with an open ASD at baseline, this difference was 97.2% versus 99.6% (p = 0.118). In patients with a closed VSD, estimated survival for those with versus those without PAH was 93.1% and 99.1%, respectively (p = 0.021; log rank test, not correcting for multiple testing). In patients with an open VSD at baseline, this difference was 96.7% versus 98.7% (p= 0.299). Median (range) estimated mortality for the patients with Eisenmenger’s syndrome was 20.6% (14.5-26.7%), and for other patients with cyanosis 16.6% (2.7-30.5%). After adjusting for age and sex, this was not significantly different. In patients with Eisenmenger’s syndrome, mortality was not significantly different according to underlying defect (ASD, VSD, or other).

42


Right ventricular function and pulmonary artery pressure

Among patients with an unclosed ASD, increased sPAP was associated with an increased prevalence of right ventricular dysfunction (patients with Eisenmenger’s syndrome excluded; figure 3). Logistic regression showed that, after adjusting for age and sex, each increase in sPAP of 1 mm Hg, increased the probability of right ventricular dysfunction by a factor of 1.073 (95% CI 1.045 to 1.102; p < 0.001).

Figure 2. Kaplan-Meier curves for 5 subgroups of patients. Panel A: patients with an ASD. Panel B: patients with a VSD. PAH=Pulmonary Artery Hypertension.

75%

80%

85%

90%

95%

100%

0 1 2 3 4 5 6

Eisenmenger (75.4%)

99 16 24 12 2

229 25 52 30 9

292 33 137 93 13

332 45 340 164 15

Follow-up (years)

Surv

ival

Patients remaining at risk

Closed, PAH (94.8%)

Open, PAH (97.2%)Closed, no PAH (98.4%)Open , no PAH (99.6%)

Open, no PAH (98.7%)

75%

80%

85%

90%

95%

100%

0 1 2 3 4 5 6

Follow-up (years)

Patients remainingat risk

224 32 257 27 77

240 35 313 39 83

Eisenmenger (82.6%)

Closed, PAH (93.1%)

Open, PAH (96.7%)

Closed, no PAH (99.1%)

183 22 181 16 64

96 9 95 5 41

Surv

ival

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Figure 3. Right ventricular (RV) dysfunction versus systolic pulmonary artery pressure (sPAP) in atrial septal defect (patients with Eisenmenger’s syndrome not included). The lines depict the predicted probabilities (the fitted values in a logistic regression model) for RV function as function of pulmonary artery pressure. The upper line represents the probability of having a moderate or poor RV function; the lower line that of having a poor function. Thus, at each level of sPAP, the vertical distances above, in between and below the two lines represent the probabilities of having good, moderate and poor RV function, respectively.

Table 3: Cyanotic patients: Eisenmenger versus non-Eisenmenger

non-Eis Eis P-value

N 138 231

Age, Median (I.Q.) 28 (22-35) 30 (24-38) 0.075

Females, N (%) 81(59%) 148 (64%) 0.179

Oxygen saturation at rest, Median (I.Q.) 84 (79-88) 82 (78-87) 0.095

History of major bleeding, N (%) 4 (3%) 37 (17%) < 0.001

History of thromboembolism (%) 11 (8%) 29 (13%) 0.224

Eis=Eisenmenger syndrome; MCV=Mean Cell Volume; Ht=Hematocrit; I.Q.=interquartile range

The lines depict the predicted probabilities (the fitted values in a logistic regression model) for right ventricular function as function of pulmonary artery pressure. The upper line represents the probability of having a moderate or poor RV function; the lower line that of having a poor function. Thus, the vertical distances above, in between, and below the two lines measure the probabilities of having good, moderate, respectively, poor RV function. PAP=Pulmonary Artery Pressure; RV=Right Ventricular

Figure 3: Right ventricular dysfunction versus systolic pulmonary artery pressure in ASD (Eisenmenger patients not included)

44


Cyanosis with and without the Eisenmenger syndrome

In table 3, baseline characteristics of patients having cyanosis with and without Eisenmenger’s syndrome are compared. The prevalence of a history of major bleeding events was much higher in patients with Eisenmenger’s syndrome. The multivariate logistic regression model, which included as variables resting oxygen saturation, age and sex, revealed that patients with Eisenmenger’s syndrome had a 22-fold increased probability of having a history of major bleeding events compared to patients with another cyanotic defect (OR 22.4, 95% CI 3.0 to 167.6, p=0.002).

DiscussionThe data bank of the Euro Heart Survey on congenital heart disease in adults allowed us to study the epidemiology of PAH in association with a cardiac septal defect in a large cohort. PAH appeared to be present in an unexpectedly high number of patients, the majority of them being seen at specialised centres. Among the patients with an open heart defect, PAH was associated with an eightfold increased probability of functional limitations. Similarly, functional limitations were present amongst patients with persisting PAH despite defect closure. Mortality was particularly high in patients with Eisenmenger’s syndrome: one in five of these patients died during the over 5-year follow-up period of the study. Furthermore, patients with Eisenmenger’s syndrome had an increased frequency of major bleeding events compared to the remainder of the patients with cyanosis. Finally, PAH was associated with right ventricular dysfunction.

Considering the importance of prevention of PAH in the management of patients with a septal defect, the high prevalence of PAH among the patients of this study is remarkable. In almost one out of every three patients with an unclosed septal defect PAH was present, although the sPAP was also increased in one out of every eight patients with a closed defect. It should be emphasised, however, that most of these patients were treated at referral centres. Our estimates are, therefore, not representative of the general population of patients with septal defects and higher than what has been reported by others. In a recent study of a general population of adult patients with congenital heart disease, it was found that 6.2% of patients with septal defects had PAH.5

In addition, it should be realised that our cohort largely reflects past medical practice. Patients > 40 years lived through their youth before operative closure of septal defects had become a relatively safe procedure. Since then, diagnosis, screening and treatment have continued to improve. It might, therefore, be expected that PAH will become increasingly rare. However, it cannot be excluded that the increase of prevalence with age is related to the process of aging in itself. In that case, a strong decline in PAH prevalence will be unlikely, given the fact that patients are getting older.

The presence of PAH was associated with clinical manifestations, even before the stage of Eisenmenger’s physiology. There was a clear relation with reduced exercise capacity, both in patients with a closed and in those with an open defect. In the latter group of patients, we

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found a strong correlation between NYHA functional class and pulmonary artery pressure: the higher the sPAP, the more functional limitations.

The haemodynamic mechanisms leading to PAH are different in patients with an ASD compared with those with a VSD. In a non-restrictive VSD, the pulmonary circulation is exposed to systemic pressure in systole directly after birth.6 In the case of an ASD, the pathogenic condition is hypercirculation and “volume overload” in the pulmonary circulation, which induces PAH after a much more protracted course.7, 8 Our findings do seem to confirm that an ASD leads to problems relatively later in life, but we found no indication that PAH has a less unfavourable impact on outcome in patients with one defect than in those with the other.

An important haemodynamic consequence of PAH is its negative effect on right ventricular function,9 as was apparent in the patients with ASD in our study: the probability of right ventricular dysfunction increased with higher sPAP values.

Once pulmonary artery pressure has reached systemic levels and Eisenmenger’s physiology with shunt reversal has developed, mortality is high, as has been found in all studies that have followed-up patients with Eisenmenger’s syndrome.9-13 The poor outcome is largely due to the effects of cyanosis and the compensatory mechanisms it induces, in particular erythrocytosis. We tried to assess the roles of cyanosis on the one hand and severe pulmonary hypertension and vascular pathology on the other hand. The finding that major bleeding events were substantially more frequent in patients with Eisenmenger’s syndrome than in the remaining patients with cyanosis is probably related to the fragile and dilated pulmonary vessels in patients with Eisenmenger’s syndrome.14, 15

Limitations

Apart from the general limitations inherent in a large retrospective multicentre study, it should be emphasised that the cohort of this study consisted of a selected group of patients, with an over-representation of patients treated at tertiary referral centres. Further, the survey was not designed to specifically study PAH, and the data set was restricted to a limited number of variables, which precluded adjusting for all possible confounding factors. In particular, we had no information on the age at closure for patients with defects that had been closed before study entry. Thus, we were not able to evaluate whether the high prevalence of PAH among patients with closed defects could be related to the timing of the intervention. Also, we were not able to reliably estimate the haemodynamic “size” of the shunt, and thus could not analyse the relation of the size of the shunt and the occurrence of PAH. Finally, it should be noted that the group of patients with cyanosis was a heterogeneous one with many different underlying defects.

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ConclusionThe Euro Heart Survey on adult congenital heart disease shows that PAH remains a risk factor for the long-term clinical course of congenital heart septal defects. In this selected group of patients, mostly attending specialised centers, PAH was unexpectedly common and associated with worse functional status, more rapid clinical deterioration and enhanced risk of death among patients with Eisenmenger’s syndrome. Whether the prevalence of PAH will decline due to improved diagnostics and earlier treatment of CHD remains speculative.

Reference List 1 Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilen U, Kaemmerer H, Moons P, Meij-

boom F, Popelova J, Laforest V, Hirsch R, Daliento L, Thaulow E, Mulder B. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005;26:2325-33.

2 Engelfriet P, Tijssen J, Kaemmerer H, Gatzoulis MA, Boersma E, Oechslin E, Thaulow E, Popelova J, Moons P, Meijboom F, Daliento L, Hirsch R, Laforest V, Thilen U, Mulder B. Adherence to guidelines in the clinical care for adults with congenital heart disease: the Euro Heart Survey on adult congenital heart disease. Eur Heart J 2006;27:737-45.

3 McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmo-nary artery systolic pressure among echocardiographically normal subjects. Circulation 2001;104:2797-802.



6 Hoffman JI, Rudolph AM. The natural history of ventricular septal defects in infancy. Am J Cardiol 1965;16:634-53.

7 Wood P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J 1958;46:755-62.

8 Campbell M Natural history of atrial septal defect. Br Heart J 1970;32:820-6.

9 Stein PD, Sabbah HN, Anbe DT, Marzilli M. Performance of the failing and nonfailing right ventricle of patients with pulmonary hypertension. Am J Cardiol 1979;44:1050-5.

10 Daliento L, Somerville J, Presbitero P, Menti L, Brach-Prever S, Rizzoli G, Stone S. Eisenmenger syndrome. Factors relating to deterioration and death. Eur Heart J 1998;19:1845-55.

11 Niwa K, Perloff JK, Kaplan S, Child JS, Miner PD. Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus, univentricular heart. J Am Coll Cardiol 1999;34:223-32.

12 Cantor WJ, Harrison DA, Moussadji JS, Connelly MS, Webb GD, Liu P, McLaughlin PR, Siu SC. Determinants of survival and length of survival in adults with Eisenmenger syndrome. Am J Cardiol 1999;84:677-81.

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13 Saha A, Balakrishnan KG, Jaiswal PK, Venkitachalam CG, Tharakan J, Titus T, Kutty R. Prognosis for patients with Eisenmenger syndrome of various aetiology. Int J Cardiol 1994;45:199-207.

14 Edwards JE. Functional pathology of the pulmonary vascular tree in congenital cardiac disease. Circula-tion 1957;15:164-96.

15 Wagenvoort CA, Nauta J, van der Schaar PJ, Weeda HW, Wagenvoort N. Effect of flow and pressure on pulmonary vessels. A semiquantitative study based on lung biopsies. Circulation 1967;35:1028-37.

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44Chapter 4

Pulmonary arterial hypertension associated with a congenital heart defect: Advanced medium-term medical treatment stabilizes clinical condition

Mariëlle GJ Duffels, Rosa LE van Loon, Rolf MF Berger, Anco Boonstra,

Anton Vonk Noordegraaf, Barbara JM Mulder.

Congenit Heart Dis 2007; 242-249


AbstractObjective: Pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD), and especially Eisenmenger syndrome, is associated with impaired exercise tolerance and reduced quality of life. In this study, we describe medium-term follow-up of adult patients with PAH associated with CHD, treated in a single center with different types of advanced medication.

Design: The treatment and clinical course of 15 patients (11 female, median age 53, range 28-74 years) with PAH associated with CHD, is retrospectively described. Data on patient characteristics, exercise test, right heart catheterization and type of advanced therapy were collected from medical files. Advanced medical therapy consisted of either intravenous prostacyclin, or endothelin receptor antagonists, or phosphodiesterase-5-inhibitors. Additional therapy was started in case of persistent clinical deterioration or insufficient improvement with monotherapy.

Results: All patients (10 patients with Eisenmenger syndrome, 5 patients with a closed defect and PAH) were exposed to different durations of advanced medication. Median period of treatment was 2.5 (range 0.7-6.3) years. Atrial septal defect, type secundum, was the most frequent underlying diagnosis (n=10). Most patients (n=9) received a combination of advanced medical therapy. Six-minute walk distance (6-MWD) remained unchanged with an increase of 44±78 m. (p=0.2) and 41± 80 m. (p=0.3) compared to baseline after respectively 1 and 2 years of treatment. Younger age was associated with better performance (β= -7 m. per year, p<0.05), patients younger than 45 years showed a greater improvement in 6-MWD after two years of treatment (p<0.05). During a mean follow-up of 23 (range 4-58) months, mean pulmonary arterial pressure (PAP) (53± 24 to 49± 17 mmHg, p=0.3) and pulmonary vascular resistance (PVR) (770± 1090 to 650± 444 dynes s/cm5, p=0.7) showed no deterioration.

Conclusion: Advanced treatment strategies in patients with PAH associated with CHD are useful. The treatment effect seems to be one of disease stabilization and decreasing the rate of deterioration. Younger age was associated with a greater improvement of 6-MWD.

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IntroductionIn the context of congenital heart defects (CHD), pulmonary arterial hypertension (PAH) may develop as a consequence of a systemic-to-pulmonary shunt. Increased systemic-to-pulmonary shunting, pulmonary blood flow and shear stress cause elevated pulmonary vascular resistance (PVR) and PAH. These changes may ultimately lead to a reversal of the systemic-to-pulmonary shunt accompanied by cyanosis1, the so-called Eisenmenger syndrome.2 Survival in patients with PAH associated with CHD is considerably better than in patients with idiopathic PAH.3 Nonetheless, PAH associated with CHD, and especially Eisenmenger syndrome, is associated with impaired exercise tolerance and exertional dyspnea which may significantly reduce quality of life.4 Moreover, it carries a high risk of mortality in a relatively young patient population with very limited treatment options.5, 6 Once Eisenmenger syndrome is present, surgical closure of the defect is no longer a therapeutic option.7, 8 In the last decade, new medical treatment strategies, so-called advanced medication, such as (intravenous) prostacyclin, endothelin receptor antagonists (ERA) and phosphodiesterase-5-inhibitor (PDE-5), have substantially improved the situation of patients with other forms of PAH.9-11 Recent studies have demonstrated a short-term positive treatment effect of either intravenous prostacyclin, ERA or PDE-5 in patients with PAH associated with a CHD.11-18 However, medium-term effects of these treatment strategies are scarce.15, 16, 19-21 We describe medium-term follow-up of adult patients with PAH associated with CHD, who received different types of advanced medication.

MethodsFor this retrospective study, we selected all adult patients with PAH associated with CHD who were treated with advanced medication since 2000 at the VU Medical Center, Amsterdam, the Netherlands. The diagnosis was established by means of a multidisciplinary diagnostic protocol.22 PAH was defined as a mean pulmonary arterial pressure (PAP) above 25 mmHg, invasively measured.23 Advanced medical therapy consisted of either intravenous prostacyclin (epoprostenol) or, ERA (bosentan, sitaxentan, ambrisentan) or PDE-5 (sildenafil). Type of advanced medication depended on WHO functional class and the availability of therapy at that moment. Additional therapy was started in case of persistent clinical deterioration or insufficient improvement with monotherapy at the physicians’ discretion. All consecutive patients gave informed consent for advanced medical therapy.

Data on patient characteristics and follow-up parameters were obtained by reviewing the medical files. The following parameters were collected: gender, age, underlying cardiac diagnosis, whether or not the underlying defect had been closed, World Health Organisation (WHO) functional class, 6-minute walk distance 24, transcutaneously measured systemic oxygen saturation breathing room air at rest, right-heart catheterization data, and type of advanced therapy. Patients underwent right-heart catheterisation to obtain right ventricular systolic pressure, pulmonary capillary wedge pressure and mean PAP including pharmacologic

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pulmonary vasodilatory testing for pulmonary vascular responder status. Total pulmonary vascular resistance (PVR) was calculated using cardiac output (CO) and mean PAP. Cardiac output was measured invasively using the Fick method. All these parameters were scored at baseline and during follow-up. All reviewed patients were treated with advanced mono- or combination therapy and changes in advanced medication were noted. Follow-up time was defined as the period between start of treatment and the last follow-up date.


The descriptive data are presented as mean with standard deviation or as median with range, when appropriate. The two-tailed Student t test for paired samples was performed for the comparison of PAP, PVR and 6-MWD between baseline and values of 6, 12, 24 months and maximum follow-up. The unpaired t-test was used to analyse differences between intravenous and oral treatment and differences between patients with Eisenmenger syndrome and those with a closed defect with PAH. The relation between age and 6-MWD was studied by linear regression. A p-value <0.05 was considered statistically significant.

Results

Population

Baseline characteristics of the 15 adult patients (4 male and 11 female) with PAH associated with CHD are displayed in table 1. Median age at the time of analysis was 53 years (range 28-74 years). Of these 15 patients, 10 patients had Eisenmenger syndrome, and 5 had a closed defect with PAH. Patients were exposed to different durations of advanced medical

Table 1. Baseline characteristics of VUMC patients (n=15) with CHD

Total(n=15)

Eisenmenger syndrome (n=10)

Closed defect (n=5)

Age (years) median (range) 53 (28-74) 52 (28-74) 53 (29-72)

Men (%) 27 40 0

Length of follow up (years) median (range) 2.5 (0.7-6.3) 2.2 (0.7-6.3) 3.0 (0.7-3.9)

At inclusion (mean ±SD)

PAP systol (mmHg) 84 ±32 76±25 100±41

PAP diastol (mmHg) 33 ±15 30±5 38±26

PAP mean (mmHg) 51 ±22 47±11 62±38

6-minute walk test (m) 421 ±138 416±161 436±64

Oxygen saturation (%) 93 ±4 92±4 97±1

NYHA classification, median (range) 3 (2-4) 3 (2-4) 3 (2-3)

CHD=congenital heart disease, PAP=pulmonary arterial pressure

52


treatment. The total cohort was treated for a median period of 2.5 (range 0.7-6.3) years, and 6 patients were followed for >2 years.

Table 2 shows the distribution of underlying congenital heart defects and the type of advanced medical therapy. Various heart defects were present: atrial septal defect, primum (ASD I, n=1) or secundum (ASD II, n=10), ventricular septal defect (VSD, n=1), patent ductus arteriosus (PDA, n=1), tetralogy of Fallot (ToF, n=1) and aortopulmonary window (n=1). ASD II was the most frequent underlying diagnosis. Monotherapy was given first line, other advanced drugs were added during the course of the observation period. Most of the patients (n=8) received a combination of advanced medical therapy. Combination therapy consisted most frequently (44%) of an ERA combined with a PDE-5. There were 2 reasons for starting additional therapy, persistent clinical deterioration or insufficient improvement with monotherapy.

Four patients reported adverse events associated with advanced treatment (bosentan, epoprostenol and sildenafil). Three of these patients discontinued therapy prematurely and continued with another form of advanced therapy. Cessation was due to 1) increasing oedema during bosentan treatment 2) recurrent catheter-related infections during intravenous prostacyclin treatment and 3) persistent gastric complaints during the use of sildenafil. The fourth patient was treated with intravenous prostacyclin and developed a catheter-related infection, requiring antibiotic therapy. Death occurred in 2 patients with an ASD II. One patient, 54 years (patient no. 14) with Eisenmenger syndrome died suddenly due to documented ventricular tachycardia after 11/2 years of treatment. The other patient, 72 years (patient no. 3), with a closed ASD II, died as a result of progressive heart failure after 3 years of treatment. For those patients who died, the last available measurements were used for analysis.

Six-minute walk test

Figure 1 depicts the individual changes in 6-MWD during advanced medical treatment over the first year. At baseline, 6-minute walk test was available in 11 patients with a mean 6-MWD of 421 ± 138 (n=11). The 6-MWD increased with a mean of 44± 78 during the first 6 months of treatment (p=0.2). After 1 year of treatment, 6-MWD remained unchanged with an increase of 29 ± 56 m. (p=0.2) compared to baseline. Figure 2 depicts the individual changes in 6-MWD over the whole follow-up period. After 2 and 4 years of treatment, 6-MWD remained stable with a mean increase of 41± 80 m. (p=0.3) and 57± 73 m. (p=0.3) respectively compared to baseline.

Younger age was associated with better performance at 6-MWD during the first two years of treatment (β= -7 m. per year, p<0.05). After two years of treatment, patients younger than 45 years showed a mean improvement of 91 ± 19 m. while patients older than 45 years showed a mean worsening of -60 ± 11 m. (p<0.05). Improvement in 6-MWD was not associated with baseline 6-MWD neither with baseline PAP. No difference in 6-MWD was observed between males and females or among different forms of underlying CHD.

53

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Patient No.

Sex Age,yr

Defect Eisenmenger NYHA Medication initial

Secundary Tertiary Quartary

Syndrome or closed defect with PAH

1 Female 53 ToF Closed defect 2 Bosentan

2 Female 41 VSD Eisenmenger syndrome 2 Bosentan Sildenafil, after 9 mo

31 Female 72 ASD II Closed defect 3 Bosentan Ambrisentan, after 28 mo

4 Female 37 ASDI Closed defect 3 Bosentan Sildenafil, after 18 mo

5 Female 48 ASD II Eisenmenger syndrome 3 Bosentan Sildenafil, after 12 mo

6 Female 28 Sinus venosus defect Eisenmenger syndrome 3 Bosentan* Epoprostenol*, after 7 mo Remodulin, after 7mo Sildenafil, after 3 mo

7 Male 53 ASD II Eisenmenger syndrome 3 Epoprostenol Bosentan, after 60 mo

8 Male 66 ASD II Eisenmenger syndrome 3 Sitaxentan

9 Male 51 ASD II Eisenmenger syndrome 4 Epoprostenol Sildenafil*, after 42 mo

10 Female 29 Aortopulmonary window Closed defect 3 Epoprostenol Sildenafil, after 28 mo


12 Female 53 ASD II Eisenmenger syndrome 2 Bosentan

13 Female 62 PDA Closed defect 3 Bosentan* Epoprostenol*, after 1 mo


15 Female 75 ASD II Eisenmenger syndrome 4 Sildenafil

Table 2. 1 patient deceased, * discontinued medication, ToF: Tetralogy of Fallot, VSD: Ventricular septal defect, ASD II: Atrial septal defect, type secundum, ASD I: Atrial septal defect, primum, PDA: patent ductus arteriosus, PAH: Pulmonary arterial hypertension, NYHA: New York Heart Association functional class, mo: months.

0

100

200

300

400

500

600

700

Baseline 3 6 9 12Follow-up (months)

6-m

inut

e w

alk

dist

ance

(m.)

patient 1patient 2patient 4patient 5patient 6patient 8patient 10patient 11patient 12patient 14 †patient 15

Figure 1. Six-minute walk test in individual patients (n=11) with pulmonary arterial hypertension associated with a congenital heart defect during the first year of treatment.

54


Patient No.

Sex Age,yr

Defect Eisenmenger NYHA Medication initial

Secundary Tertiary Quartary

Syndrome or closed defect with PAH

1 Female 53 ToF Closed defect 2 Bosentan

2 Female 41 VSD Eisenmenger syndrome 2 Bosentan Sildenafil, after 9 mo

31 Female 72 ASD II Closed defect 3 Bosentan Ambrisentan, after 28 mo

4 Female 37 ASDI Closed defect 3 Bosentan Sildenafil, after 18 mo


6 Female 28 Sinus venosus defect Eisenmenger syndrome 3 Bosentan* Epoprostenol*, after 7 mo Remodulin, after 7mo Sildenafil, after 3 mo

7 Male 53 ASD II Eisenmenger syndrome 3 Epoprostenol Bosentan, after 60 mo


9 Male 51 ASD II Eisenmenger syndrome 4 Epoprostenol Sildenafil*, after 42 mo

10 Female 29 Aortopulmonary window Closed defect 3 Epoprostenol Sildenafil, after 28 mo


12 Female 53 ASD II Eisenmenger syndrome 2 Bosentan

13 Female 62 PDA Closed defect 3 Bosentan* Epoprostenol*, after 1 mo


15 Female 75 ASD II Eisenmenger syndrome 4 Sildenafil

Table 2. 1 patient deceased, * discontinued medication, ToF: Tetralogy of Fallot, VSD: Ventricular septal defect, ASD II: Atrial septal defect, type secundum, ASD I: Atrial septal defect, primum, PDA: patent ductus arteriosus, PAH: Pulmonary arterial hypertension, NYHA: New York Heart Association functional class, mo: months.

Figure 2. Six-minute walk test in individual patients (n=14) with pulmonary arterial hypertension associated with a congenital heart defect during treatment with a mean follow-up of 2.5 years (range 0.7-6.3 years).

0

100

200

300

400

500

600

700

Baseline 12 24 36 48 60Follow-up (months)

6-m

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.)

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patient 3 †

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patient 5

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patient 7

patient 8

patient 9

patient 10

patient 11

patient 12

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patient 15

55

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Moreover, during follow-up no difference in mean 6-MWD was seen between patients treated with either mono- or combination therapy (at 12 months, p=0.3). Oxygen saturation, breathing room air, remained unchanged compared to baseline (92± 4%) after 12 and 24 months of treatment, respectively 92 ± 4% (p=0.7) and 91 ± 8% (p=0.3).

Seven patients (patient no. 3, 5, 6, 7, 8, 12 and 14) showed a temporary deterioration of their 6-MWT compared to baseline (at respectively 36, 12, 12, 48, 3, 3 and 12 months). Deterioration was not associated with occurrence of an adverse event or previous change in therapy. One patient’s clinical condition declined due to a pulmonary embolism (patient no. 5). Four other patients who initially deteriorated, subsequently improved spontaneously. Of the remaining 2 patients, no further follow-up data was available at the moment of analysis.

Catheterisation data and WHO functional class

At baseline, during invasive pharmacologic testing, none of the patients showed pulmonary vasoreactivity responder status. After a mean follow-up of 23 (range 4-58) months, there was a slight reduction in mean PAP (53±24 to 49±17 mmHg, p=0.3) and PVR (770±1090 to 650±444 dynes.s/cm5, p=0.7). CO remained stable during treatment. Most patients (n=9) were in WHO functional class III prior to initiation of advanced treatment. During follow-up, WHO functional class remained stable during advanced treatment in most cases.

Discussion This is one of the first studies describing the medium-term results of treatment with different types of advanced medication in patients with PAH associated with CHD. From this analysis, it appears that the medium-term treatment effect of either mono- or combination therapy with intravenous prostacyclin, ERA or PDE-5 is one of disease stabilization and decreasing the rate of deterioration. Younger age was associated with a greater treatment effect. In particular, patients younger than 45 years showed a significantly greater improvement in 6-MWD.

All patients in this study started on one of the available types of advanced medication. We found a slight improvement in 6-MWD after 6 months of treatment, which is in accordance with recent studies.11-18 However, medium-term effects of these treatment strategies are scarce. In our study population, the slight increase of 6-MWD appeared to stabilize during 1, 2 and 4 years of treatment. This positive trend is in line with few other small studies among patients with Eisenmenger syndrome or PAH associated with CHD.15, 16, 19, 21, 25

No changes in oxygen saturation were seen. This indicates that advanced medical therapy in patients with Eisenmenger syndrome does not negatively influence the direction of the shunt, which could theoretically occur if systemic resistance would drop.

In several patients, treatment with an additional drug was necessary at some point during follow-up because of either clinical deterioration or suboptimal response to monotherapy. No difference in mean 6-MWD was seen between patients treated with either mono- or

56


combination therapy but patient numbers were too small to compare subgroups. Although prostacyclin, ERA and PDE-5 inhibitors work through different pathways, there may be important synergistic effects between them. Small studies in patients with either idiopathic PAH, or PAH due to connective tissue disease have suggested beneficial effects of combined therapy.26, 27

A remarkable finding was that younger age was associated with greater treatment effect. Patients younger than 45 years showed a significantly greater improvement at 6-MWD after two years of treatment compared to patients older than 45 years. A possible explanation might be the longer period of high pulmonary pressure in older patients. In other words, older patients probably have a more advanced stage of the disease.

Most patients with Eisenmenger syndrome in our study had an ASD as underlying defect. The known prevalence of Eisenmenger syndrome in septal defects is lower for ASD patients than for patients with VSD or AVSD.4, 28-30 This selection of patients may be the result of this specific referral center which, at the time of patient inclusion, was mainly known as a referral center for patients with idiopathic pulmonary hypertension. The diagnosis ASD was often made only during the diagnostic work up in this referral center.22 Because development of PAH is a late complication of untreated ASD, we found a relatively high age in our population compared to other studies.4 It should be noted that the findings in this study, therefore, may not be entirely representative for all patients with Eisenmenger syndrome.

Limitations

Limitations of this study include the small sample size and the retrospective analysis. As a consequence, patients underwent testing (exercise testing and right heart catheterizations) for clinical indications, and there was some variability in the frequency of this testing, resulting in some lacking data. Other limitations of this study include the lack of a control group and the heterogeneity of treatment regimens. Conclusions about the optimal advanced treatment strategy, using mono- or combination therapy, cannot be made, indicating the necessity for investigations describing larger study populations.

ConclusionOur analysis indicates that advanced treatment strategies in patients with either Eisenmenger syndrome or a closed heart defect with PAH, might be beneficial. The treatment effect seems to be one of disease stabilization and decreasing the rate of deterioration. An age younger than 45 years, was associated with greater improvement of 6-MWD. However, a larger patient population is needed to better assess the long-term therapeutic effects and the usefulness of combination therapy among patients with PAH associated with CHD.

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Reference List 1 Granton JT, Rabinovitch M. Pulmonary arterial hypertension in congenital heart disease. Cardiol Clin

2002;20:441-57, vii.

2 Wood. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J 1958;46:755-62.

3 Berman EB, Barst RJ. Eisenmenger’s syndrome: current management. Prog Cardiovasc Dis 2002;45:129-38.

4 Duffels M.G.J., Engelfriet P.M., Berger R.M.F., van Loon R.L.E., Hoendermis E., Vriend J.W.J., van der Velde E.T., Bresser P., Mulder B.J.M. Pulmonary arterial hypertension in congenital heart disease: An epidemiologic perspective from a Dutch registry. Int J Cardiol 2007;120:198-204.

5 Duffels M.G.J., Berger R.M.F., Bresser P., de Bruin-Bon H.A.C.M., Hoendermis E., Bouma B.J., Mulder B.J.M. Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity. Netherlands Heart Journal 2006;14:165-70.

6 Engelfriet P.M., Duffels M.G.J., Moller T.Boersma E.Tijssen J.G.P., Thaulow E, Gatzoulis MA, Mulder B.J.M. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007;93:682-7.




10 McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82.

11 Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006;151:851-5.

12 Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Effect of the oral endothelin antagonist bosentan on the clinical, exercise, and haemodynamic status of patients with pulmonary arterial hyper-tension related to congenital heart disease. Heart 2005;91:1447-52.


14 Fernandes SM, Newburger JW, Lang P, Pearson DD, Feinstein JA, Gauvreau K, Landzberg MJ. Useful-ness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger physiology. Am J Cardiol 2003;91:632-5.

15 Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associ-ated congenital heart defects. Circulation 1999;99:1858-65.


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17 Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deck-ers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004;25:2243-78.

18 Dharmadhikari A, Airoldi F, Tzifos V, Sheiban I, Pathak L, Bansal N. Sildenafil in the treatment of atrial septal defect with moderate to severe pulmonary arterial hypertension. Eur Heart J 2004;25.

19 Benza RL, Rayburn BK, Tallaj JA, Coffey CS, Pinderski LJ, Pamoukian SV, Bourge RC. Efficacy of bosen-tan in a small cohort of adult patients with pulmonary arterial hypertension related to congenital heart disease. Chest 2006;129:1009-15.

20 Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Long-term oral bosentan therapy in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2006.

21 Adriaenssens T, Delcroix M, Van DK, Budts W. Advanced therapy may delay the need for transplanta-tion in patients with the Eisenmenger syndrome. Eur Heart J 2006.

22 Roeleveld RJ, Boonstra AB, Voskuyl AE, Bronzwaer JG, Marques KM, vonk NA. [Diagnosis of pulmo-nary hypertension: experiences with 187 patients referred to the VU Medical Center]. Ned Tijdschr Geneeskd 2004;148:82-8.


24 ATS statement: guidelines for the six-minute walk test Am J Respir Crit Care Med 2002;166:111-7.

25 Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Long-term oral bosentan therapy in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2007;93:350-4.

26 Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004;24:1007-10.

27 Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R, Block LH. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hyper-tension. Chest 2003;123:1293-5.

28 Vogel M, Berger F, Kramer A, exi-Meshkishvili V, Lange PE. Incidence of secondary pulmonary hyper-tension in adults with atrial septal or sinus venosus defects. Heart 1999;82:30-3.

29 Craig RJ, Selzer A. Natural history and prognosis of atrial septal defect. Circulation 1968;37:805-15.

30 Konstantinides S, Geibel A, Olschewski M, Gornandt L, Roskamm H, Spillner G, Just H, Kasper W. A comparison of surgical and medical therapy for atrial septal defect in adults. N Engl J Med 1995;333:469-73.

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Figure 4. Mean (SEM) change from baseline of 6MWD in adults and children55

Chapter 5

Long-term effect of bosentan in adults versus children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: Does the beneficial effect persist?

Rosa LE van Loon, Elke S Hoendermis, Mariëlle GJ Duffels, Anton Vonk Noordegraaf,

Barbara JM Mulder, Hans L Hillege, Rolf MF Berger

American Heart Journal 2007; 154: 776-782


AbstractBackground: Data on long-term response to bosentan in adults and especially children with pulmonary arterial hypertension (PAH) associated with systemic-to-pulmonary shunt are scarce.

Methods: We studied bosentan efficacy in 30 patients (20 adults, 10 children) with the disease at short (4 months), and long-term follow-up (through 2.7 years). World Health Organization functional class (WHO class), transcutaneous oxygen saturation (TcSO2) and 6-minute walk distance (6MWD) were assessed at baseline, 4 months, 1 year, 1.5 years and at latest follow-up (median 2.7 years).

Results: At baseline, children tended to have more severe disease compared to adults with regard to WHO class and congenital heart defects. At 4 months’ follow-up, WHO class and 6MWD significantly improved in both adults and children. During long-term follow-up, this improvement persisted through 1 year, but declined thereafter in the total group. In the children a progressive decline in exercise capacity was observed from 1-year follow-up, whereas in the adults, improvement lasted longer. No change from baseline was seen in TcSO2. Three (10%) patients died, 2 (7%) discontinued bosentan and 5 (17%) required additional PAH therapy (of whom 1 eventually died). One and 2-year persistence of beneficial bosentan effect was 68% and 43% (total group), 78% and 57% (adults), and 50% and 20% (children).

Conclusions: Our experience with bosentan suggests short-term improvement in both adults and children with PAH associated with systemic-to-pulmonary shunt. At long-term follow-up a progressive decline in beneficial bosentan effect was observed. The decline appeared most pronounced in the pediatric patients, who, in this study, tended to have more severe disease at baseline.

62


IntroductionPulmonary arterial hypertension (PAH) is a progressive and ultimately lethal pulmonary vascular disease which can be idiopathic or associated with underlying conditions. Eisenmenger syndrome is the most advanced form of PAH associated with congenital heart disease due to systemic-to-pulmonary shunt. It develops as a result of chronically increased pulmonary blood flow and pressure which ultimately cause increased pulmonary vascular resistance, permanent reversal of the shunt and hypoxemia.1 Although survival estimates are reported to be better compared to patients with idiopathic PAH (iPAH), morbidity,2-4 including decreased exercise capacity, is high5 and, therefore, stresses the need for therapy.

Bosentan, a dual endothelin receptor antagonist, has been introduced as an important new oral PAH therapy targeting over-expression of endothelin-1. It currently is an accepted and effective short and long-term treatment for iPAH and PAH secondary to connective tissue disease.6-8 Due to the similarities in pulmonary vascular changes and increased endothelin-1 levels seen in different types of PAH,9, 10 it could be expected that patients with PAH associated with systemic-to-pulmonary shunt will benefit from this medication as well.

Short-term improvements in functional class, exercise capacity and hemodynamics at 4 months follow-up were recently demonstrated in a placebo-controlled randomized trial with bosentan in adults with PAH associated with systemic-to-pulmonary shunt, without compromising systemic oxygen saturation (and thus not increasing right-to-left shunting).11 Long-term bosentan effects, however, are less well known. Four non-controlled studies have suggested persisting improvement at follow-up of 1 to 2 years,12-15 whereas a report by Apostolopoulou et al. suggested a decline in exercise capacity after 2 years follow-up.16

The use of bosentan in pediatric patients with PAH associated with systemic-to-pulmonary shunt has yet to be evaluated. Most non-controlled studies reporting results with bosentan in patients with PAH associated with systemic-to-pulmonary shunt have included adult patients.12-19 Very few studies exist which report response to bosentan in pediatric PAH. Moreover, they include only small numbers of children with systemic-to-pulmonary shunt and mainly describe short-term follow-up.20-23

The purpose of this study was to assess short (4 months) and long-term bosentan effects (through 2.7 years) on functional class and exercise capacity in both adults and children with PAH associated with systemic-to-pulmonary shunt. To assess differences between adults and children we subsequently analyzed bosentan efficacy separately within both groups.

Methods

Patients

Between November 2002 and February 2007, a cohort of 30 patients (20 adults, 10 children) with PAH associated with congenital or surgically created systemic-to-pulmonary shunt and treated with bosentan (Tracleer;Actelion Pharmaceuticals;Switzerland), had standardized

63

Chap

ter 5Long

-term effect of b

osentan in adults versus children


follow-up at two Dutch tertiary medical referral centers for pulmonary hypertension. Eight patients included in the series, initially received bosentan as part of a clinical trial.11 All patients or patients’ parents/caregivers gave informed consent and institutional review board approval was obtained for the study.

Patients with Eisenmenger syndrome or PAH after corrected systemic-to-pulmonary shunt who were clinically stable in World Health Organization functional class (WHO class) II or worse, were selected for treatment. Eisenmenger syndrome was diagnosed echocardiographically as right-to-left shunting through the shunt-defect. In cases with corrected shunts, mean pulmonary arterial pressure (mPAP) of more than 25 mmHg (measured invasively by cardiac catheterization), established the diagnosis of PAH. Patients with severe left ventricular dysfunction and/or pulmonary venous congestion (measured invasively or assessed echocardiographically) were excluded.

In 1 child bosentan was started with the aim of ending epoprostenol therapy, because of recurrent problems with central venous lines for epoprostenol delivery. In 1 adult it was started in addition to previously initiated epoprostenol, because of failure to improve from WHO class IV. In the total cohort, supportive medication present at start of bosentan therapy, including diuretics, ACE-inhibitors, digoxin and/or antithrombotic agents, was continued unchanged during follow-up.

Treatment regimen

In the adult patient group, bosentan target dose was 125 mg twice daily. Pediatric patients received bosentan according to body weight: 31.25 mg (10 to 20kg weight), 62.5 mg (20 to 40kg) or 125 mg (weight over 40kg) twice daily.20 During the first 4 weeks of treatment patients received half the target dose once daily. After 4 weeks this was increased to the target dose, if bosentan was well tolerated.

Study assessments

Patients were followed within routine clinical practice, using a standardized protocol for assessments at baseline and during follow-up. Data were collected at baseline, 4 months, 1 year, 1.5 years and at most recent follow-up (median 2.7 years, range 2.0-3.4 years).

Assessments included WHO class, transcutaneous oxygen saturation at rest (TcSO2), heart rate, blood pressure and 6-minute walk distance (6MWD). Additional outcome parameters included survival and persistence of beneficial bosentan effect, as previously defined by Rosenzweig et al22 (freedom from death, lung or heart lung transplant, atrial septostomy, discontinuation of treatment or requirement of additional PAH therapy: epoprostenol, trepostinil, sildenafil). Because criteria for the introduction of add-on therapy are not clearly defined for patients with PAH associated with systemic-to-pulmonary shunt, not all patients in this series in whom initial improvement in 6MWD disappeared during follow-up, received such additional therapy. Therefore, we subsequently extended the definition by including

64


decline in 6MWD during follow-up to below baseline value. Liver function tests, hemoglobin and hematocrit were tested monthly in order to screen for adverse effects.


Data are presented as mean±SD or median and range, where appropriate. Change in 6MWD from baseline is expressed as mean with 95% confidence intervals (95%CI). To compare changes from baseline to each of the follow-up visits, paired Student’s t tests (6MWD, TcSO2, blood pressure, heart rate and hematocrit) and Wilcoxon’s rank sum tests (WHO class) were used. Kaplan-Meier curves were applied to depict survival and persistence of beneficial bosentan effect.

To analyze differences between measurements in adults and children, independent samples t tests (continuous variables) and Mann-Whitney U tests (WHO class, type of heart defect) were used. The log-rank test was used to assess differences in survival and persistence of beneficial bosentan effect between adults and children.

The association between age group (adults versus children) and indicators of disease severity at baseline (type of heart defect, WHO class, 6MWD, invasive hemodynamics) and persistence of beneficial bosentan effect was assessed by means of the log-rank test. Subsequently, a multivariate Cox regression analysis was performed to assess variables found to be predictive in the univariate analysis. All p-values were two-tailed and those <0.05 were considered significant.

Results

Patients

Baseline characteristics are summarized in Table 1. Ventricular septal defect (VSD) was the most common heart defect (53%), and frequently associated with additional shunt-defects, such as atrial septal defect (ASD) and persistent ductus arteriosus (PDA). An isolated ASD was seen in 19% of all patients, all of whom were adults. Twenty-six patients (87%) had classical Eisenmenger syndrome, 6 of these with a shunt before and 20 after the level of the tricuspid valve. The remaining 4 patients had persistent PAH despite closure of their systemic-to-pulmonary shunts years earlier. One child with VSD and PDA had undergone corrective surgery in the past. Because of clinical deterioration 1 year after corrective surgery, an ASD had to be created (9 years prior to study enrolment). This patient was categorized as having a pre-tricuspid shunt. More post-tricuspid shunt-defects were present in the children than in the adults(80% and 60% respectively).

At baseline, all children and 90% of the adults were in WHO class III or IV.(Table 1, Figure 1) Children had a worse WHO class (p=0.04) and higher hematocrit (p=0.05) compared to the adults. Baseline 6MWD and TcSO2 tended to be lower in the children, although not reaching statistical significance.

65

Chap

ter 5Long

-term effect of b



Baseline cardiac catheterization was performed in 27 out of 30 patients.(Table 2) Children tended to have worse baseline hemodynamics compared to adults: the ratio of mean pulmonary arterial pressure to mean systemic arterial pressure (mPAP/mSAP) was significantly higher in the children (p=0.03). Cardiac index and pulmonary-to-systemic blood flow ratio tended to be lower in the children, though not reaching statistical significance.

Table 1. Patient demographics and baseline exercise capacity

All patientsn=30

Adultsn=20

Childrenn=10

Female 20 (67) 12 (60) 8 (80)

Age at start Bosentan (years) 30.2 ± 16.0 39.3 ± 10.2 * 11.8 ± 4.8 *

31.2 (4.7; 59.3) 39.0 (26.7; 59.3) 12.8 (4.7; 17.3)

Congenital heart defect

ASD isolated 5 (16) 5 (25) 0

VSD isolated 9 (30) 7 (35) 2 (20)

VSD ± ASD ± PDA 7 (23) 3 (15) 4 (40)

PDA 2 (7) 0 2 (20)

cAVSD 3 (10) 2 (10) 1 (10)

DORV 2 (7) 2 (10) 0

Complex 2 (7) 1 (5) 1 (10)

Shunt patency

Open 26 (87) 17 (85) 9 (90)

Pre-tricuspid shunt 6 5 1

Post-tricuspid shunt 20 12 8

Closed † 4 (13) 3 (15) 1 (10)

WHO class * *

II 2 (7) 2 (10) 0

III 22 (73) 16 (80) 6 (60)

IV 6 (20) 2 (10) 4 (40)

TcSO2 (%) 87 ± 7 89 ± 6 83 ± 9

6MWD (m) 367 ± 101 388 ± 99 326 ± 95

Ht 0.51 ± 0.10 0.48 ± 0.08 * 0.56 ± 0.10 *

Data are presented as n (%), mean ± SD, median (range) as appropriate. ASD = atrial septal defect, VSD = ventricular septal defect, PDA = patent ductus arteriosus, cAVSD = complete atrioventricular septal defect, DORV = double outlet right ventricle, Complex = truncus arteriosus (n=1), tetralogy of Fallot with Potts anastomosis (n=1). Pre-tricuspid shunt: ASD. Post-tricuspid shunt: VSD, PDA, cAVSD, DORV, complex. † Shunt closed: VSD+ASD (n=1), truncus arteriosus (n=1), DORV (n=1), tetralogy of Fallot and Potts anastomosis (n=1). TcSO2 = transcutaneous oxygen saturation at rest, 6MWD = 6-minute walk distance. * significant difference between adults and children: Age p=0.00, WHO class p=0.04

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Follow-up assessments

Median duration of bosentan treatment was 2.2 years (range 0.04-3.4 years) in the total group, 2.1 years (range 0.4-3.1) in the adults and 2.4 years (range 0.04-3.4) in the children. Twenty-six(87%) patients received long-term treatment (median 2.4 years, range 1.0-3.4 years). Four(13%) patients had a follow-up of less than 1 year (median 0.5 years, range 0.04-0.7 years) due to death (n=2) or discontinuation of treatment (n=2).

2

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baseline 4 months 1 year 1.5 years 2.7 years

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WHO 4WHO 3WHO 2

* p=0.001 * p=0.001 * p=0.002 p=0.06

Figure 1. WHO functional class during follow-up for total group. † Follow-up visits at 1.5 and 2.7 years: after addition of sildenafil in 3 and 4 patients respectively. Number of patients in each class is indicated in the bars. * significant change from baseline

Table 2. Baseline hemodynamic characteristics

All patients Adults Children

mPAP (mmHg) 64 ± 21 64 ± 24 62 ± 8

mPCWP (mmHg) 7 ± 3 7 ± 2 8 ± 3

mPAP/mSAP 0.87 ± 0.19 0.80 ± 0.18 * 0.98 ± 0.13 *

mRAP (mmHg) 5 ± 2 5 ± 2 6 ± 3

CI (l/min/m2) 2.8 ± 1.1 2.9 ± 1.2 2.6 ± 0.9

Qp/Qs 0.91 ± 0.35 0.98 ± 0.37 0.79 ± 0.28

PVRix (WU.m2) 32.9 ± 15.9 33.3 ± 18.2 32.3 ± 11.7

SVRix (WU.m2) 34.9 ± 15.8 39.3 ± 16.7 26.8 ± 10.8

PVR/SVR 1.07 ± 0.64 0.92 ± 0.57 1.3 ± 0.70

CI = cardiac index, mRAP = mean right atrial pressure, mPAP = mean pulmonary artery pressure, mPCWP = mean pulmonary capillary wedge pressure, mSAP = mean systemic arterial pressure, mPAP/mSAP = ratio between mean pulmonary and systemic arterial pressure, PVRix = pulmonary vascular resistance index, SVRix = systemic vascular resistance index, WU = Woods units. * significant difference between adults and children: mPAP/mSAP p=0.03

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Short-term follow-up

At 4 months after bosentan initiation, 1 child had died (after 2 weeks). Cause of death was hemoptysis associated with acute circulatory failure. In the remaining 29 patients clinical condition and exercise capacity improved significantly from baseline.(Figures 1 and 2) When analyzed separately, significant improvement in WHO class and 6MWD was present in both the adults and children.(Figures 3 and 4)

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Long-term follow-up

During longer follow-up 2 more children died: after 8.4 months and 3.1 years. Causes of death were, respectively, progressive right ventricular failure and infection of the epoprostenol delivery system leading to sepsis.

Overall, the initial WHO class improvement persisted during long-term follow-up at 1 and 1.5 years. However, at the latest follow-up visit, improvement could no longer be demonstrated in the remaining total cohort.(Figure 1) When analyzed separately, a similar pattern was seen mainly in the children.(Figure 3)

The initial increase in 6MWD persisted in the total cohort during 1 year follow-up, but declined after longer treatment duration.(Figure 2) The decline in 6MWD particularly appeared to be the case in the children. A significant difference between adults and children was observed at 1 and 1.5 years (p=0.01 and p=0.04 respectively)(Figure 4)

During follow-up, additional sildenafil was started in 5 patients (17%, 4 adults, 1 child) after a median bosentan treatment duration of 1.3 years (range 1.0-2.4 years). Based on the

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physician’s discretion, reasons for starting additional therapy were decreased 6MWD and/or decline or failure to improve in clinical condition (decline to WHO class IV, remaining in WHO class III). After addition of sildenafil, 1 patient improved, 1 remained stable and 3 patients worsened, of whom 1 adult required addition of intravenous epoprostenol.

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Figure 3. WHO functional class during follow-up for adults (A) and children (B). † Follow-up visit at 1.5 years after addition of sildenafil in 3 adults and at 2.7 years in 3 adults and 1 child. * significant change from baseline. There was a significant difference between adults and children at baseline (p=0.04) and a tendency to difference at 2.7 years (p=0.07)

A

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TcSO2, heart rate, blood pressure and hematocrit did not change from baseline through last follow-up.

Survival is illustrated in Figure 5. The difference in survival between children and adults was not statistically significant. Using Rosenzweig criteria for persistence of beneficial bosentan effect, three events occurred in the children (3 deaths, of which 1 death occurred 9 months after additional sildenafil) and 6 events in the adults (2 patients discontinued bosentan, 4 patients required additional sildenafil). One and 2-year persistence of beneficial bosentan effect according to Rosenzweig criteria was respectively 79% and 71%(total group), 78% and 65%(adults), and 80% and 80%(children). Persistence of beneficial bosentan effect, including decline in 6MWD, revealed lower 1 and 2-year event-free estimates and was significantly different between adults and children (p=0.04).(Figure 6)

In contrast, baseline indicators of disease severity (type of heart defect, WHO class, 6MWD and hemodynamics) could not be demonstrated to be predictive for persistence of beneficial bosentan effect. Furthermore, the predictive value of age group remained unchanged after adjustment for different indicators of disease severity in a multivariate Cox regression analysis.

All but 1 patient tolerated bosentan treatment. This adult patient discontinued treatment after half a year because of side effects consisting of nasopharyngeal complaints. A second adult discontinued treatment because he experienced lack of improvement with bosentan therapy.

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Figure 4. Mean (SEM) change from baseline of 6MWD in adults and children. † At 1.5 years follow-up 2 adults and at 2.7 years follow-up 2 adults and 1 child underwent a 6-minute walk test after addition of sildenafil. * significant change from baseline, Significant difference between adults and children at 1 year (p=0.01) and 2.7 years follow-up (p=0.04)

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DiscussionThis study, to our knowledge, is the first to report long-term response to bosentan through 2.7 years of follow-up in both adults and children with PAH associated with systemic-to-pulmonary shunt. Our results demonstrate short-term improvement in functional class and exercise capacity in both patient groups, which is in congruence with previous reports. During longer follow-up, improvement in 6MWD, the major outcome parameter in PAH studies, persisted up to 1 year, but declined thereafter. Separate analyses within the adult and pediatric group indicated that the decline was most pronounced in the children. One and 2-year persistence of beneficial bosentan effect was 68% and 43%(total group), 78% and 57%(adults) and 50% and 20%(children).

The improvement in 6MWD for up to 1 year corresponds with the 1-year follow-up reports of bosentan efficacy in adults with PAH associated with systemic-to-pulmonary shunt.12-

14 From 1.5 years follow-up, however, we observed a decline in exercise capacity in our total

Figure 5. Survival from baseline stratified for adults and children

Figure 6. Persistence of beneficial bosentan effect including decline in 6MWD, stratified for adults and children.Difference adults vs children p=0.04

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group. In the only other study evaluating a minimum of 2 years follow-up, Apostolopoulou et al reported a similar observation, noticing a decline in 6MWD and peak oxygen consumption to baseline value in 19 patients with PAH associated with congenital heart disease.16

Reports of long-term bosentan efficacy in iPAH have used event-free estimates, including addition of therapy as event, to assess persistence of bosentan effect.6, 7 In these series, additional prostanoid and/or sildenafil therapy, suggesting insufficient effect of bosentan, was given in up to 44% of patients during 2 years of follow-up.6, 7 In our study, additional therapy was given less frequently (17% of patients). This can be explained by the lack of data on the use of add-on therapy for PAH associated with systemic-to pulmonary shunt, which is in contrast to the presence of aggressive guidelines for iPAH.24 In order to make more appropriate comparisons, we studied persistence of beneficial bosentan effect, an outcome parameter which integrated addition of other PAH therapy and decline in 6MWD. Using this outcome measure, we found 1 and 2-year event-free estimates in our adult group(78% and 57% respectively) which are in line with those reported by Provencher et al (63% and 45%) and McLauglin et al (85% and 70%) for adults with iPAH treated with bosentan.6, 7 In contrast, our pediatric 1 and 2-year event-free estimates were markedly lower(50% and 20%).

One may speculate that the worse outcome in the children was caused by more severe disease. This is supported by our observation of worse baseline hemodynamics in this group. The greater percentage of post-tricuspid shunts may also have played a role in their less favorable outcome. Advanced pulmonary vascular disease appears to develop more frequently and more rapidly in patients with uncorrected post-tricuspid than pre-tricuspid shunt-defects.25 Although our analyses suggested that the predictive value of age was independent of underlying cardiac pathology and disease severity, our study may not have been powered sufficiently to conclude this.

The three deaths out of 10 children may be another reflection of more end-stage disease in this age group. Survival rates in Eisenmenger syndrome are reported to be favorable compared to iPAH (30-40 vs 2.8 years respectively).2-4 However, they are mainly derived from cohorts of adult patients. This obviously will have lead to a selection bias, excluding patients who died before reaching adulthood due to more severe disease.

In the assessment of patients with PAH, 6MWD is considered to be the most important outcome parameter.26, 27 In evaluating children, the 6-minute walk test has been suggested to be reliable in children above 7 years of age.26 In our experience with pediatric patients, we noticed that previous training resulted in reproducible 6-minute walk tests.

The present study is limited by the relatively small number of patients and the lack of a control group. Therefore, this study cannot ascertain whether bosentan may have long-term effect on the natural decline of these patients. Data collection within routine clinical practice and recent start of therapy resulted in some unavailable follow-up measurements in the adults. However, in PAH associated with systemic-to-pulmonary shunt, studies with larger numbers of patients hardly are available.

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In conclusion, this study depicts long-term experience in daily clinical practice with bosentan in patients with PAH associated with systemic-to-pulmonary shunt. It raises important questions about persistence of beneficial effects with bosentan monotherapy. Short-term improvements ultimately declined during long-term follow-up and persistence of beneficial bosentan effect decreased progressively over time. The decline in treatment effect was most pronounced in the children. The difference in treatment effect between adults and children may have been confounded by differences in cardiac pathology and disease severity. Our analyses, however, could not demonstrate this, possibly due to a lack of power. In our adult patient group beneficial effects lasted longer and treatment effect was comparable to reports in iPAH patients. However, the clinical importance of a 1-2 year treatment effect in iPAH compared to Eisenmenger patients is greatly affected by the large difference in survival between these two groups(2.8 vs 30-40 years respectively). Larger prospective studies, including children, are warranted in order to confirm these preliminary long-term results and to assess the use of add-on therapy.

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Reference List 1 Berman EB, Barst RJ. Eisenmenger’s syndrome: current management. Prog Cardiovasc Dis 2002;45:129-

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2 Cantor WJ, Harrison DA, Moussadji JS, Connelly MS, Webb GD, Liu P, McLaughlin PR, Siu SC. Determinants of survival and length of survival in adults with Eisenmenger syndrome. Am J Cardiol 1999;84:677-81.

3 D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, . Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343-9.

4 Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant 1996;15:100-5.


6 McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, Rainisio M, Simonneau G, Rubin LJ. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005;25:244-9.

7 Provencher S, Sitbon O, Humbert M, Cabrol S, Jais X, Simonneau G. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J 2006;27:589-95.


9 Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-9.

10 Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, Reid LM, Tuder RM. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:25S-32S.

11 Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RMF, Lauer A, Chiossi E, Landzberg M, for the Bosentan Randomized Trial of Endothelin Antagonist Therapy-. Bosentan therapy in patients with Eisenmenger syndrome: A multicenter, double-blind, randomized, placebo-controlled study. Circula-tion 2006;114:48-54.

12 Benza RL, Rayburn BK, Tallaj JA, Coffey CS, Pinderski LJ, Pamoukian SV, Bourge RC. Efficacy of bosen-tan in a small cohort of adult patients with pulmonary arterial hypertension related to congenital heart disease. Chest 2006;129:1009-15.

13 D’Alto M, Vizza CD, Romeo E, Badagliacca R, Santoro G, Poscia R, Sarubbi B, Mancone M, Argiento P, Ferrante F, Russo MG, Fedele F, Calabro R. Long term effects of bosentan treatment in adult patients with pulmonary arterial hypertension related to congenital heart disease (Eisenmenger physiology): safety, tolerability, clinical, and haemodynamic effect. Heart 2007;93:621-5.

14 Sitbon O, Beghetti M, Petit J, Iserin L, Humbert M, Gressin V, Simonneau G. Bosentan for the treat-ment of pulmonary arterial hypertension associated with congenital heart defects. Eur J Clin Invest 2006;36 Suppl 3:25-31.

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16 Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2007;93:350-4.


18 Gatzoulis MA, Rogers P, Li W, Harries C, Cramer D, Ward S, Mikhail GW, Gibbs JS. Safety and tolera-bility of bosentan in adults with Eisenmenger physiology. Int J Cardiol 2005;98:147-51.

19 Kotlyar E, Sy R, Keogh AM, Kermeen F, Macdonald PS, Hayward CS, McNeil KD, Celermajer DS. Bosentan for the treatment of pulmonary arterial hypertension associated with congenital cardiac disease. Cardiol Young 2006;16:268-74.

20 Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, Bingaman D, Nguyen N, Gaitonde M, van Giersbergen PL. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmo-nary arterial hypertension. Clin Pharmacol Ther 2003;73:372-82.

21 Maiya S, Hislop AA, Flynn Y, Haworth SG. Response to bosentan in children with pulmonary hyperten-sion. Heart 2006;92:664-70.

22 Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005;46:697-704.

23 Gilbert N, Luther YC, Miera O, Nagdyman N, Ewert P, Berger F, Lange PE, Schulze-Neick I. Initial experience with bosentan (Tracleer) as treatment for pulmonary arterial hypertension (PAH) due to congenital heart disease in infants and young children. Z Kardiol 2005;94:570-4.

24 Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005;26:858-63.

25 Ivy D Diagnosis and treatment of severe pediatric pulmonary hypertension. Cardiol Rev 2001;9:227-37.

26 Garofano RP, Barst RJ. Exercise testing in children with primary pulmonary hypertension. Pediatr Cardiol 1999;20:61-4.

27 Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hyper-tension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000;161:487-92.

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66Chapter 6

Down patients with Eisenmenger syndrome: Is bosentan treatment an option?

Mariëlle GJ Duffels, Jeroen C Vis, Rosa LE van Loon, Rolf MF Berger, Elke S Hoendermis,

Arie PJ van Dijk, Berto J Bouma, Barbara JM Mulder.

Int J Cardiol 2009;134: 378-383


AbstractBackground: Favorable results of treatment with bosentan in patients with Eisenmenger syndrome are available. However, data in Down patients are lacking. In this study, we evaluate the therapeutic role of bosentan treatment in Down patients with Eisenmenger syndrome.

Methods: In this open-label study, 24 Down patients (>18 years) with Eisenmenger syndrome (17 males) were treated with bosentan. Their mean age was 38 years (range 19-55 years). All Down patients were evaluated at baseline and during follow-up with laboratory tests, six-minute walk test (6-MWT), Doppler echocardiography, and quality of life questionnaires.

Results: The median follow-up of Down patients treated with bosentan was 11.5 months (range 3- 23 months). Induction of oral bosentan therapy was well tolerated among all 24 Down patients. Bosentan treatment was generally well tolerated. No serious adverse drug reactions were noted. Median 6-MWT increased from 296 meters (range 40- 424 meters) to 325 meters (range 84-459 meters, p<0.05) after 12 weeks. After 26 and 52 weeks of treatment with bosentan, median 6-MWT distance was 276 meters (range 140-462 meters, n=15, p=0.6) and 287 meters (range 131-409 meters, n=7, p=0.3), respectively. Quality of life questionnaire scores remained stable during treatment.

Conclusion: Also patients with Down syndrome may benefit from bosentan treatment when they have Eisenmenger syndrome. Medical treatment appears to be safe and the treatment effects do not deviate from those observed in Eisenmenger patients without Down syndrome.

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Introduction

Trisomy 21 is the most common single chromosome abnormality at birth, occurring in about 1 in 800 births.1, 2 The frequency of congenital heart disease in patients with Down’s syndrome is very high with a prevalence between 40%-60%.3, 4 Atrioventricular septal defect is the most common congenital heart disease among patients with Down’s syndrome followed by ventricular septal defect.4 In the context of congenital heart disease, pulmonary arterial hypertension (PAH) may develop as a consequence of a systemic-to-pulmonary shunt. Increased pulmonary vascular resistance may ultimately lead to a reversal of the systemic-to-pulmonary shunt leading to cyanosis, the so called Eisenmenger syndrome. In patients with Down’s syndrome, PAH has been suggested to develop earlier and to have a more violent course.5, 6

Eisenmenger syndrome carries a high risk of morbidity in a relatively young patient population and has limited therapeutic options. 7, 8 Once the Eisenmenger syndrome has occurred, repair of the underlying defect is contraindicated. The right ventricle will be unable to cope with the progressively increased afterload due to the high pulmonary vascular resistance and will fail.9 Dyspnoea, arrhythmia and premature death are common features of PAH.10, 11 Exercise tolerance and quality of life in patients with PAH related to congenital heart disease has been shown to be low.12, 13

New medical treatment strategies, such as prostacyclin, endothelin receptor antagonists (bosentan) and phosphodiesterase-5- inhibitors have substantially improved the clinical status and life expectancy of patients with PAH.14-17 The BREATHE-V study showed that bosentan is safe and well tolerated in patients with Eisenmenger syndrome without any worsening of pulmonary-to-systemic shunting.18 However, in Down patients with Eisenmenger syndrome, the therapeutic role of bosentan is not known, as patients with Down syndrome were generally not included in these studies. It is important to establish the applicability of bosentan in this group specifically, as Down patients born in the seventies frequently have uncorrected congenital heart disease.

The aim of this study was to evaluate the safety and tolerability of oral bosentan therapy in Down patients with Eisenmenger syndrome by assessing its effects on clinical status and functional capacity.

Methods

Patients

In January 2005, the Interuniversity Cardiology Institute of the Netherlands (ICIN) initiated a treatment protocol for adult patients with PAH associated with congenital heart disease, including patients with Down’s syndrome. The diagnosis Eisenmenger syndrome was based on clinical findings and echocardiographic features. Patients could have any of the following congenital heart disease: univentricular heart, patent ductus arteriosus and septal defects such

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as ventricular septal defect, atrial septal defect, or atrioventricular septal defect. Patients with obstruction of the right ventricular outflow tract, pulmonary valve or pulmonary arteries or patients receiving prostacyclin, glibenclamide or cyclosporin treatments were excluded from the protocol.

Study protocol

This was an uncontrolled open-label study. All Down patients were evaluated at baseline, WHO functional class, laboratory tests, six-minute walk test (6-MWT), Doppler echocardiography, and quality of life questionnaires were assessed. The 6-MWT, commonly used as measure for treatment effect in PAH, was performed according to the guidelines of the American Thoracic Society with continuous pulse oximetry monitoring.19 The 6-MWT is easy to administer, well tolerated and reflects activities of daily living.20 In this study, in analogy with paediatric PAH patients, we selected Down patients who were capable of performing an adequate and reproducible 6-MWT. To consider the effect of a learning-curve, the 6-MWT at baseline was performed twice, the second 6-MWT was used as baseline value. Doppler echocardiography was used to establish the Eisenmenger syndrome and to estimate the systolic right ventricular and pulmonary arterial pressure (sPAP) by means of the tricuspid regurgitation jet velocity. Quality of life was assessed by means of the Minnesota Living with Heart Failure Questionnaire and by means of the SF-36.21 The Minnesota Living with Heart Failure Questionnaire rates patients’ perceptions of how much their disease affects the physical, socio-economic, and psychological aspects of daily life. For the present study, the term “heart failure” was replaced by “pulmonary arterial hypertension” as reported in other studies.22, 23 The SF-36 is a generic multi-item questionnaire comprising 36 questions addressing 8 areas representing physical functioning, role functioning physical, bodily pain, general health perceptions, vitality, social functioning, role functioning emotional, and mental health. Both quality of life questionnaires were filled in by the parents or guardians of the patient.

After performing baseline evaluation, oral bosentan was administered at an initial dose of 62.5 mg twice daily. Four weeks later, after measurement of oxygen saturation and liver function tests, bosentan was increased to a maximum dose of 125 mg twice daily, if well tolerated. At 12 weeks of treatment 6-MWT, and at 26 and 52 weeks 6-MWT and Doppler echocardiography were repeated.

Safety was evaluated at 12, 26 and 52 weeks of treatment by monitoring adverse events such as flushing and nasal congestion, vital signs, pulse oximetry, and premature treatment discontinuations. Resting systemic arterial oxygen saturation was measured transcutaneously by non-invasive finger pulse oximetry after 5 min of absolute rest in the sitting position. Liver function tests and haemoglobin levels were checked every two weeks during the first two months and monthly thereafter. According to the bosentan summary of product characteristics, the standard threshold for liver function abnormality of > 3 times the upper limit of normal was applied.

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The descriptive data are presented as median with range. Changes from baseline to 12, 24, 52 and 76 weeks were evaluated with a paired t test for continuous variables (and with Wilcoxon’s rank sum test for categorical variables). A value of p<0.05 was considered to be significant.

Results

Patients

Between January 2005 and May 2007, 28 Down patients with Eisenmenger syndrome, were enrolled in the standardised treatment protocol. All patients were able to perform an adequate and reproducible 6-MWT. None of these patients had undergone previous repair of their congenital heart defect.

Subsequently, 24 Down patients, 17 (71%) males and 7 (29%) females, aged 19-55 years (mean 38 years), started bosentan treatment. Four patients were excluded from the standardized treatment protocol. One patient could not swallow the tablet, in one patient hypothyroidism was diagnosed at the time of initiation of bosentan and in two patients, the health insurance company refused to reimburse the medication. These four patients were not considered in the analysis.

Baseline characteristics

Table 1 summarizes the patients’ baseline characteristics. Fifteen patients had an atrioventricular septal defect of whom one patient had a concurrent patent ductus arteriosus, nine patients had a ventricular septal defect of whom two patients had a concurrent patent ductus arteriosus. All patients experienced dyspnea, impairment of exercise tolerance, and were in functional class III or IV as assessed by the WHO functional class. All patients were cyanotic with a median transcutaneous oxygen saturation of 84% (63 - 94%) at rest. Baseline median systolic

Table 1. Baseline characteristics of Down patients with Eisenmenger syndrome (n=24)

Mean age (years) 38 (19-55)

Men, n (%) 17 (71)

Underlying diagnosis, (n)

- Ventricular septal defect 7

- Ventricular septal defect, patent ductus arteriosus 2

- Atrioventricular septal defect 14

- Atrioventricular septal defect, patent ductus arteriosus 1

Median pulmonary arterial pressure (mmHg) 89 (76-110)

Median oxygen saturation (%) 84 (63-94)

Median six minute walk distance (meters) 296 (40-424)

Median NT-pro-BNP (ug/L) 339 (35-4414)

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pulmonary arterial pressure (sPAP) was 89 mmHg (range 76 - 110 mmHg). Baseline median 6-MWT was 296 meters (40 - 424 meters).

Safety and tolerability

All 24 Down patients tolerated induction of oral bosentan therapy without any signs of decreased oxygen saturation. Median transcutaneous oxygen saturation remained virtually unchanged compared to baseline (84%, range 63-94%, n=24) after 12, 26 and 52 weeks of bosentan treatment (84%, range 67-92%, n=22; 81%, range 73-92%, n=15 and 85%, range 75-87%, n=7, respectively). Patients started bosentan 125 mg twice daily after receiving bosentan 62.5 mg twice daily for four weeks. Bosentan treatment was generally well tolerated. No serious adverse drug reactions were noted. No liver function abnormalities (> 3x upper limit of normal) were observed. Flushing was reported occasionally but resolved within two weeks without regimen changes. Headache was reported once and resolved within two weeks after dose reduction; whereupon the 125 mg twice daily dose was resumed without reoccurrence of the problems. No patient required additional therapy because of progression of disease. One patient died of a brain abscess after 14 months of treatment.

Treatment effect

The median follow-up of Down patients treated with bosentan was 11.5 months (range 3- 23 months). Figure 1 depicts the changes in 6-MWT of all 24 patients during bosentan treatment. During the first 12 weeks, 17 of 24 (71%) patients showed an increase of 6-MWT. Median

Figure 1. Six-minute walk test in individual Down patients with Eisenmenger syndrome (n=24) during treatment with a median follow-up of 11.5 months (range 3- 23 months). †: 1 patient deceased due to a brain abcess.

6 minute walk test down patients (n=24)1 patient deceased due to brain abcess

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6-MWT increased from 296 meters (range 40-424 meters, n=24) at baseline to 325 meters (range 84-459 meters, n=24, p<0.05) after 12 weeks. After 26 and 52 weeks of treatment with bosentan, median 6-MWT distance was 276 meters (range 140-462 meters, n=15, p=0.6) and 287 meters (range 131-409 meters, n=7, p=0.3). After 1 year, 2 of 7 (29%) patients still showed an increased 6-MWT compared to baseline. Median NT-pro-BNP remained stable (339 ng/L, range 35-4414 ng/L, n=23) after 12, 26 and 52 weeks of bosentan treatment (respectively 415 ng/L, range 43-5714 ng/L, n=18; 670 ng/L, range 50-3148 ng/L, n=12 and 276 ng/L, range 28-728 ng/L, n=7).

Quality of life

Ten patients completed the SF-36 and the Minnesota Living with PAH Questionnaire at baseline and 7 patients after 1 year of follow-up. Down patients with Eisenmenger syndrome had a significantly worse quality of life compared to the general Dutch population in 3 of the 8 areas assessed by the SF-36: physical functioning, general health and vitality ( all p<0.05) (figure 2). The only area of quality of life in which patients with Down syndrome and Eisenmenger syndrome did have better outcome than the general population was role limitations caused by emotional problems (p<0.01). In figure 3, the follow-up of 3 areas: physical functioning, general health and vitality of the SF-36 are shown. Quality of life of these 3 areas remained stable during treatment.

Figure 2. Down patients with Eisenmenger syndrome show a significantly worse quality of life for the areas: physical functioning, general health and vitality of the SF-36 (all <p<0.05) compared to the general population (population norm). Data shown represent the percentage impairment of the SF-36 quality of life questionnaire.

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Figure 3a, b and c shows the follow up of the three SF-36 areas: physical functioning, general health and vitality during bosentan treatment. Data shown represent the percentage impairment of the SF-36 quality of life questionnaire.

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In figure 4 the median total Minnesota Living with PAH Questionnaire is shown. The response of therapy on quality of life could be evaluated in 7 patients after 1 year follow-up. Scores on the total questionnaire range from 0 to 105, with higher scores reflecting a worse perceived quality of life. As shown in this figure, the mean Minnesota Living with PAH Questionnaire scores remained stable during treatment (28, range 6-67 and 26, range 0-67, p=0.7).

Figure 4 show the median total Minnesota Living with pulmonary arterial hypertension questionnaire. Scores on the total questionnaire range from 0 to 105, with higher scores reflect a worse perceived quality of life. The Minnesota Living questionnaire scores remained stable during treatment.

DiscussionTo our knowledge, this is the first study on the effect of bosentan in Down patients with Eisenmenger syndrome. Therapy with bosentan proved to be safe and well tolerated. Our results suggest that exercise tolerance improved during the first 3 months of bosentan treatment, after which 6-MWT slowly returned to baseline value.

Congenital heart defects in Down patients born in the seventies, often remained surgically uncorrected. Therefore, Eisenmenger syndrome is more common among these patients compared to non-Down patients with congenital heart disease. To prevent the exclusion of Down patients from evolving treatment, it is important to establish the applicability of new medical therapy in this group specifically. In non-Down patients, the 6-MWT is a generally accepted outcome parameter to assess the treatment effect in PAH. Its value in Down patients has not been validated and its applicability in this group is questionable due to a lack of understanding or cooperation. However, it can reliably be used in paediatric patients from seven years of age.24 Therefore, we selected Down patients who were capable of performing

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an adequate and reproducible 6-MWT. In order to correct for a learning curve, the second of two baseline tests was used.

Similarly, quality of life questionnaires have not been validated in Down patients. In order to collect as much information as possible on the effect of bosentan treatment, we evaluated quality of life questionnaires recruited from the parents or guardians.

Therefore, outcome data were available from the 6-MWT and quality of life questionnaires. In spite of their shortcomings, we used the 6-MWT and quality of life questionnaires as outcome parameters in Down patients with Eisenmenger syndrome.

Our results showed that bosentan administration was safe and well tolerated in Down patients with Eisenmenger syndrome without increasing cyanosis or serious side effects. No patient required additional therapy for PAH. The general safety observations in this subgroup of patients with Down syndrome were in accordance with the recent studies with bosentan in non-Down patients with Eisenmenger syndrome.14, 15, 17, 25-27

Exercise tolerance assessed by the 6-MWT improved during the first 3 months of bosentan treatment. The magnitude of the observed positive treatment effect during the first 3 months in our study compared well with the observations on the 6-MWT in the other studies among patients with Eisenmenger syndrome without Down syndrome.14, 15, 17, 28 After this initial improvement, the 6-MWT appeared to return slowly to baseline. This is consistent with other studies on longer-term follow-up.29 Although patient numbers at 1 year follow-up in our study were low, the treatment effects do not deviate from those observed in Eisenmenger patients without Down syndrome.

Study limitations

Limitations of this study include the lack of a placebo group and the relatively small sample size. However, our observations are in line with other recent studies. An increase of our study sample size with longer-term follow-up is needed to better assess the duration of the therapeutic effects of bosentan.

ConclusionIn conclusion, also patients with Down syndrome may benefit from bosentan treatment when they have Eisenmenger syndrome. Medical treatment appears to be safe and the treatment effects do not deviate from those observed in Eisenmenger patients without Down syndrome.

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Reference List 1 Rasmussen SA, Wong LY, Correa A, Gambrell D, Friedman JM. Survival in infants with Down syndrome,

Metropolitan Atlanta, 1979-1998. J Pediatr 2006;148:806-12.

2 Ghaffar S, Lemler MS, Fixler DE, Ramaciotti C. Trisomy 21 and congenital heart disease: effect of timing of initial echocardiogram. Clin Pediatr (Phila) 2005;44:39-42.

3 de Rubens FJ, del Pozzo MB, Pablos Hach JL, Calderon JC, Castrejon UR. [Heart malformations in chil-dren with Down syndrome]. Rev Esp Cardiol 2003;56:894-9.

4 Freeman SB, Taft LF, Dooley KJ, Allran K, Sherman SL, Hassold TJ, Khoury MJ, Saker DM. Population-based study of congenital heart defects in Down syndrome. Am J Med Genet 1998;80:213-7.

5 Malec E, Mroczek T, Pajak J, Januszewska K, Zdebska E. Results of surgical treatment of congenital heart defects in children with Down’s syndrome. Pediatr Cardiol 1999;20:351-4.

6 Suzuki K, Yamaki S, Mimori S, Murakami Y, Mori K, Takahashi Y, Kikuchi T. Pulmonary vascular disease in Down’s syndrome with complete atrioventricular septal defect. Am J Cardiol 2000;86:434-7.

7 Duffels MGJ, Engelfriet PM, Berger RMF, van Loon RLE, Hoendermis E, Vriend JWJ, Van der Velde ET, Bresser P, Mulder BJM. Pulmonary arterial hypertension in congenital heart disease: An epidemiologic perspective from a Dutch registry. Int J Cardiol 2007;120:198-204.

8 Engelfriet PM, Duffels MG, Moller T, Boersma E, Tijssen JG, Thaulow E, Gatzoulis MA, Mulder BJ. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007;93:682-7.





13 Lane DA, Lip GY, Millane TA. Quality of life in adults with congenital heart disease. Heart 2002;88:71-5.

14 Duffels MGJ, Berger RMF, Bresser P, de Bruin-Bon HACM, Hoendermis E, Bouma BJ, Mulder BJM. Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity. Neth Heart J 2006;14:165-70.

15 Gatzoulis MA, Rogers P, Li W, Harries C, Cramer D, Ward S, Mikhail GW, Gibbs JS. Safety and tolera-bility of bosentan in adults with Eisenmenger physiology. Int J Cardiol 2005;98:147-51.



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20 Solway S, Brooks D, Lacasse Y, Thomas S. A qualitative systematic overview of the measurement prop-erties of functional walk tests used in the cardiorespiratory domain. Chest 2001;119:256-70.

21 Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, Sprangers MA, te VA, Verrips E. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998;51:1055-68.

22 Chua RF, Keogh AM FAU, Byth KF, O’Loughlin A. Comparison and validation of three measures of qual-ity of life in patients with pulmonary hypertension.

23 Cenedese E, Speich R, Dorschner L, Ulrich S, Maggiorini M, Jenni R, Fischler M. Measurement of qual-ity of life in pulmonary hypertension and its significance. Eur Respir J 2006;28:808-15.

24 Geiger R, Strasak A, Treml B, Gasser K, Kleinsasser A, Fischer V, Geiger H, Loeckinger A, Stein JI. Six-minute walk test in children and adolescents. J Pediatr 2007;150:395-9.






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77Chapter 7

Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without down’s syndrome

Mariëlle GJ Duffels, Jeroen C Vis, Rosa LE van Loon, Pythia T Nieuwkerk, Arie PJ van Dijk,

Elke S Hoendermis, Rianne HACM de Bruin-Bon, Berto J Bouma, Paul Bresser,

Rolf MF Berger, Barbara JM Mulder

Am J of Cardiol 2009; 103: 1309-1315.


AbstractPulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) due to systemic-to-pulmonary shunting is associated with a high risk of morbidity and mortality. In this retrospective study, we evaluated longer-term treatment effect of bosentan on exercise capacity and quality of life in 58 adult patients (>18 years) with PAH associated with CHD, including patients with Down syndrome. All patients were evaluated at baseline and during follow-up with laboratory tests, 6-minute walk test, quality of life questionnaires, and Doppler echocardiography. We analyzed treatment efficacy separately within patients without (n=30) and patients with Down syndrome (n=28). Median follow-up of all patients treated with bosentan was 22 months (range 3-36 months). In patients without Down syndrome, mean 6-minute walk distance (6-MWD) increased from 427 ± 97 m to 461 ± 104 m (p<0.01) after 6 months of treatment, followed by a gradual return to baseline and disease stabilization. Quality of life improved significantly during treatment and maintained during 18 months follow-up (p<0.05). In the patients with Down syndrome, 6-MWD and quality of life remained stable during treatment. In conclusion, our findings suggest that in patients without Down syndrome longer-term bosentan treatment resulted in a persistent improvement of quality of life and a stabilization of exercise capacity.

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IntroductionUntil recently, treatment options for patients with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) were limited to the avoidance and treatment of complications. A major breakthrough in the treatment of patients with PAH has been the introduction of oral endothelin receptor antagonists. Short-term treatment with bosentan has shown to improve morbidity of patients with PAH, including those with Eisenmenger syndrome.1-4 However, results on longer-term treatment response are equivocal and data on quality of life (QoL) is limited despite the importance of QoL assessment.5, 6 Although several studies reported a persistent beneficial effect of bosentan on exercise capacity7-11, other studies reported a gradual decline of exercise capacity to baseline values after 2 years of bosentan treatment.12, 13 In patients with Down syndrome, the treatment effect of bosentan is largely unknown.14 The aim of our study was to evaluate the short- and longer-term treatment effect of bosentan in adult patients with PAH associated with CHD with and without the Down syndrome, by assessing exercise capacity and QoL.

MethodsThe study population consisted of adult patients with PAH associated with CHD, including patients with Eisenmenger syndrome. Patients were divided into 2 groups: patients without Down syndrome (the “non-Down” patients) and patients with Down syndrome. Enrolled patients were diagnosed with any of the following congenital heart defects: univentricular heart, patent ductus arteriosus and septal defects such as ventricular septal defect, atrial septal defect, or atrioventricular septal defect. Patients with persistent PAH after previous closure of their CHD were also enrolled. Patients with obstruction of the right ventricular outflow tract, pulmonary valve or pulmonary arteries or patients on prostacyclin, glibenclamide or cyclosporine treatments were excluded.

We performed an retrospective study. After baseline examinations, adult patients with PAH associated with CHD were treated with bosentan according to a standardized treatment protocol (as described in more detail below). At baseline, patients’ clinical and functional status were evaluated using laboratory tests (including haemoglobin, creatinine, uric acid and NT-pro-BNP levels), 6-minute walk distance (6-MWD), QoL questionnaires, and Doppler echocardiography. To exclude other causes of PAH, lungfunction tests (spirometry, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)) were obtained. Additionally, in non-Down patients, maximal exercise capacity (peak V’O2)15 and Cardiovascular Magnetic Resonance Imaging were performed at baseline and during follow-up.

Submaximal exercise capacity was assessed using the 6-MWD, according to the guidelines of the American Thoracic Society with continuous pulse oximetry monitoring.16 To exclude the effect of a learning curve, the 6-MWD at baseline was performed twice, using the second test as baseline value. The 6-MWD was used as primary endpoint and the test was repeated every 3 months during bosentan treatment.

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QoL was evaluated by means of the SF-365 and by means of the Minnesota Living with Pulmonary Hypertension Questionnaire. The SF-36 is a well-documented, widely used and validated, self-administered QoL scoring system incorporating 36 questions. It includes 8 independent scales (scored as a number between 0 and 100) that assess the following general health concepts: physical functioning, limitations because of physical health problems (role physical), bodily pain, general health perceptions, vitality, social functioning, limitations because of emotional problems (role emotional), and mental health.5 The Minnesota Living with Pulmonary Hypertension Questionnaire rates patients’ perceptions of how much their disease affects the physical, socio-economic, and psychological aspects of daily life. Scores on the total questionnaire range from 0 to 105, with higher scores reflecting a worse perceived QoL. Both QoL questionnaires were filled in by the patient or, in case of Down syndrome, by the parent or guardian of the patient, at baseline and with regular intervals of 6 months during follow-up.

Doppler echocardiography (VIVID 7 General Electric, USA) was performed to define the heart defect and confirm the Eisenmenger syndrome, which was defined as a right-to-left shunt through the defect. Moreover, we evaluated left and right ventricular function during bosentan treatment every 6 months in both patient groups. Right ventricular function was measured by tricuspid annular plane systolic excursion and the systolic pulmonary arterial pressure was estimated by the peak velocity of the tricuspid regurgitation jet using continuous-wave Doppler.17 Tricuspid annular peak systolic velocity (TDS)18, TEI-index and contraction duration of the right ventricle were assessed using tissue Doppler imaging. Right ventricular contraction duration, corrected for heart rate, was measured from the onset of the QRS complex to the onset of early diastolic filling of the right ventricle (E).19 All echocardiographic images were acquired and recorded digitally, and analyzed offline by a single observer (HdBB).

Additionally, in non-Down patients, Cardiovascular Magnetic Resonance Imaging was used to assess ventricular volumes, ejection fraction, and stroke volume of both ventricles. At baseline and after 1 or 2 years follow-up, end-diastolic and end-systolic volumes of both ventricles were calculated by the sums of the traced contours in end-diastole and end-systole. End-diastolic volume and end-systolic volume were used to calculate stroke volume and ejection fraction.

After performing baseline evaluation, oral bosentan was administered at an initial dose of 62.5 mg twice daily. Four weeks after treatment initiation, the initial dose was increased to the target dose of 125 mg twice daily. Liver function, serum haemoglobin levels, and serum haematocrit levels were tested monthly to screen for adverse effects.

Descriptive data are presented as mean with standard deviation if normally distributed or as median with range, as appropriate. Changes from baseline to each of the follow-up visits were assessed by paired student t tests. Data for the SF-36 and Minnesota Living with Heart Failure Questionnaire were summarized by mean change from baseline to each time-point for the patients observed. A value of p<0.05 was considered to be significant.

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ResultsBetween January 2005 and June 2008, 58 adult patients with PAH associated with CHD started oral bosentan treatment. The median follow-up duration was 22 months (range 3 to 36 months). Forty-eight percent (n=28) of enrolled patients had Down syndrome. Table 1 summarizes patients’ baseline characteristics. Of the 6 non-Down patients without Eisenmenger syndrome, 3 patients had persistent PAH after previous closure of their CHD, 2 patients had refused operation and in 1 patient operative risk was deemed too high due to co-morbidity.

Table 1. Baseline characteristics of the study population

Total(n=58)

Non Down(n=30)

Down syndrome(n=28)

p-value

Age, mean (range, yrs) 42 (20-75) 47 (23-75) 38 (20-56) 0,005

Gender, male 29 (50%) 10 (33%) 19 (68%) 0,009

Eisenmenger syndrome 49 (86%) 24 (80%) 28 (100%)

Median Follow up (months) 20 (3-36) 22 (3-36) 18 (3-36) 0,9

Follow up > 6 months 53 (91%) 27 (90%) 26 (93%)

Underlying congenital heart defects

Atrial septal defect primum 2 2

Atrial septal defect secundum 3 3

Atrial septal defect sinus venosus 2 2

Ventricular septal defect 21 (+5) 14 (+2) 7 (+3)

(+ patent ductus arteriosus)

Patent ductus arteriosus 3 2 1

Univentricular Heart 4 4

Atrioventricular septal defect 16 (+1) 16 (+1)

+ patent ductus arteriosus

Transposition of the great arteries 1 1

Oxygen saturation (%) 85 ± 8 86 ± 8 84 ± 8 0,4

Six-minute walk distance at baseline (m) 371 427 ± 97 308 ± 102 <0,001

New York Heart Association class

II 3 (5%) 3 (10%) 0

III 55 (95%) 27 (90%) 28 (100%)

Systolic pulmonary arterial pressure (mmHg) 88 83 ± 22 92 ± 11 0,2

Stroke volume (ml) 72 75 ± 26 69 ± 30 0,6

Cardiac output (L/min) 5 6 ± 2 5 ± 3 0,9

Mean NT-pro-BNP (ng/L) 904 1036 ± 1634 781 ± 974 0,5

Creatinine (umol/L) 81 72 ± 16 94 ± 32 0,004

Uric acid (mmol/L) 0,5 0,5 ± 0,1 0,5 ± 0,1 0,7

Haemoglobin (mmol/L) 12 11 ± 2 13 ± 2 0,002

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Induction of oral bosentan therapy was well tolerated in both patient groups, without signs of decreasing oxygen saturation. During follow-up, 2 patients died. One non-Down patient died suddenly 4 months after treatment initiation, probably due to cardiac arrhythmia and 1 patient with Down syndrome died from a brain abscess after 14 months bosentan treatment. One non-Down patient experienced severe throat pain and in 1 non-Down patient an asymptomatic increase in liver transaminases (>3 times upper limit of normal) was observed. Both resolved within 2 weeks after dose reduction, whereupon the 125 mg twice daily dose was resumed without reoccurrence of the problems.

The individual changes in 6-MWD in non-Down patients are shown in figure 1a. In the whole group of non-Down patients, the 6-MWD increased significantly from 427 ± 97 m at baseline to 461 ± 104 m (p<0.01) after 6 months of bosentan treatment. After this initial improvement, however, 6-MWD gradually returned to baseline values in the following 6 months (p=0.1). After this first year of treatment, 6-MWD appeared to remain stable for the following 12 months (p=0.4). Subgroup analysis revealed that treatment effect persisted after 2 years in the Eisenmenger population (n=24), compared to the non-Eisenmenger population (n=6), while mean baseline 6-MWD was similar in patients with and without Eisenmenger syndrome. In the Eisenmenger patients, after 1 and 2 years of bosentan treatment, 6-MWD improved with a mean of respectively 19 ± 41 m (p=0.06) and 24 ± 35 m (p=0.07), respectively, compared to baseline.

In addition to the 6-MWD, 11 non-Down patients performed a maximal exercise capacity test (peak V’O2) at baseline and after 1 year bosentan treatment. Maximal exercise capacity test remained unchanged (15 ± 5 ml/min/kg to 17 ± 5 ml/min/kg; p=0.2) after 1 year follow-up compared to baseline. Figure 1b depicts the individual 6-MWD of patients with Down syndrome during treatment. In these patients, exercise capacity remained unchanged during bosentan treatment.

Non-Down syndrome (n=30)Six-minute walk distance during follow-up

3 6 300

100

200

300

400

500

600

700

Follow-up (months)

30 26 25 24 12 13 8

PAH , n=6Eisenmenger syndrome, n=24

6-m

inut

e w

alk

dist

ance

(m)

Down syndrome (n=28)Six-minute walk distance during follow-up

0 3 6 12 18 24 30 0

100

200

300

400

500

Follow-up (months)

27 25 25 23 14 11 5Number of patients

6-m

inut

e w

alk

dist

ance

(m)

0 12 18 24

Number of patients

Figure 1a. Six-minute walk test in non-Down patients with PAH associated with CHD at baseline and during follow-up. After the first year of treatment, 6-minute walk distance stabilized. 1b. Six-minute walk test in patients with Down syndrome with PAH associated with CHD at baseline and during follow-up. During treatment with bosentan, exercise capacity remained unchanged compared to baseline.

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Thirteen non-Down patients and 14 patients with the Down syndrome completed the SF-36 and the Minnesota Living with Pulmonary Hypertension Questionnaire. In non-Down patients, QoL improved significantly in 2 of the 8 scales assessed by the SF-36, as shown in figure 2a and b. Daily life limitations caused by physical health problems (role physical) improved significantly compared to baseline and the improvement seemed to persist during longer-term follow-up (figure 2a). In addition, vitality improved significantly after 6 months and the improvement remained until 18 months of bosentan treatment (figure 2b). In patients with Down syndrome, all 8 scales of the SF-36 remained stable. The mean Minnesota Living with Pulmonary Hypertension Questionnaire scores remained unchanged in both patient groups (33, range 6-67 and 38, range 0-67, p=0.7).

0

25

50

75

100

125

Scor

e

SF-36 Role physical score

p=0.04

p=0.02

p=0.051

Baseline 6 months 1 year 1.5 year 0

25

50

75

100Non-Down, n=14Down syndrome, n=17

Follow-up

Scor

ep=0.051

p=0.03

SF-36 Vitality score

Baseline 6 months 1 year 1.5 year Follow-up

Figure 2a and b. Quality of life scores of the two SF-36 areas: role physical and vitality during treatment with bosentan in both non-Down patients and patients with Down syndrome. Data shown represent the mean score of the SF-36 quality of life questionnaire.

Echocardiographic parameters at baseline and during treatment are shown in table 2. In general, most echocardiographic parameters remained unchanged in both groups of patients during follow-up. However, analyses of the left ventricle in non-Down patients showed that stroke volume tended to increase after 1 year bosentan treatment. Analyses of the right ventricle demonstrated an average decrease in right ventricular contraction duration after 1 year bosentan treatment in those non-Down patients whose 6-MWD improved compared to baseline (n=11). In patients with Down syndrome, 1 year treatment resulted in a significant increase in tricuspid annular peak systolic velocity (TDS).

In 9 non-Down patients we performed Cardiovascular Magnetic Resonance Imaging at baseline and after a mean follow-up of 21 ± 8 months. Of these patients, 3 patients had a previously closed CHD with persistent PAH, 1 patient had a patent ductus arteriosus and 5 patients had a ventricular septal defect. On average, exercise capacity remained stable in these patients during 6 and 12 months follow-up. Both mean end diastolic volume, and end

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systolic volume, as well as mean stroke volume and mean ejection fraction of the left and right ventricle remained stable during bosentan treatment, as shown in table 3.

NT-pro-BNP levels remained unchanged during bosentan treatment (table 2) in both patient groups. As did haemoglobin, creatinine and uric acid levels. No associations could be found between changes in 6-MWD during bosentan treatment and mean NT-pro-BNP at baseline or NT-pro-BNP changes. In addition, no relations were found between changes in 6-MWD and haemoglobin, creatinine or uric acid levels.

Table 2. Outcome parameters during follow-up

Baseline 6 months p 1 year p 2 year p

Non Down syndrome (n=30)

Echocardiography

Heart rate (bpm) 77 ± 12 71±11 0,1 75 ± 16 0,5 76±6 0,8

Stroke volume (ml) 79 ± 29 88±31 0.1 84 ± 20 0.05 82±20 0,2

Cardiac output (L/min) 6 ± 2 6±2 0.6 6 ± 2 0,2 6±2 0,3

Systolic pulmonary 93 ± 19 83±21 0,2 84 ± 20 0,7 77±22 0,1

arterial pressure (mmHg)

TEI index 0,9 ± 1 0,6±0,2 0.4 0,6 ± 0,3 0.4 0,8±0,5 0,3

Tricuspid annular plane 19 ± 5 20±6 0.4 19 ± 6 0.5 21±7 0,7

systolic excursion

Tissue doppler S right 11 ± 3 11±3 0.8 11 ± 3 0.4 10±4 0,3

ventricle

Laboratory tests (n=25)

NT-pro-BNP (ng/L) 1036 ± 1634 614±646 0.4 1271 ± 1909 0.2 1128±1269 0.9

Down syndrome (n=28)

Echocardiography

Heart rate (bpm) 77 ± 16 72±14 0,2 76 ± 12 0,9 75±13 0,9

Stroke volume (ml) 68 ± 33 74±36 0,1 67 ± 31 0,1 68±29 0,5

Cardiac output (L/min) 5 ± 3 5±2 0,7 5 ± 2 0,6 5±2 0,98

Systolic pulmonary 93 ± 11 90±16 0,1 87 ± 14 0,2 87±15 0,7

arterial pressure (mmHg)

TEI index 0,7 ± 0,3 0,6±0,2 0.07 0,7 ± 0,2 0,7 0,6±0,2 0.4

Tricuspid annular plane 18 ± 6 21±5 0,2 20 ± 4 0,1 19±4 0.5

systolic excursion

Tissue doppler S right 10 ± 2 11±2 0.1 11 ± 2 0,02 11±3 0.1

ventricle

Laboratory tests (n=27)

NT-pro-BNP (ng/L) 781 ± 974 709±793 0.1 879 ± 1025 0.09 661±524 0.08

Mean values with SD. P-values compared to baseline.

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Discussion This is the first study reporting on the effect of almost 2 years of bosentan treatment on exercise capacity and QoL in adult patients with PAH associated with CHD, including patients with the Down syndrome. In non-Down patients, we demonstrated a significant increase in exercise capacity after the first 6 months of treatment and an improvement in QoL. After the initial improvement, mean exercise tolerance declined to baseline values and finally stabilized during longer term follow-up. Improvement of QoL persisted throughout the follow-up period. In contrast, exercise tolerance and QoL remained unchanged in patients with the Down syndrome during treatment. Overall, we found no changes in cardiac function as determined by echocardiography, cardiovascular magnetic resonance and serum NT-pro-BNP levels in both groups during treatment.

The observed treatment effect of bosentan on exercise capacity in non-Down patients compares well with the observations of Apostolopoulou et al., who reported a decline in 6-MWD to baseline values in patients with PAH associated with CHD after 2 years of therapy.12 Additionally, van Loon et al. demonstrated similar findings in both adults and children with PAH associated with CHD at long-term follow-up.13 The decline in 6-MWD during treatment might be due to the development of tolerance for bosentan, as previously observed in some patients receiving epoprostenol.20 On the other hand, natural disease progression may also play a role. The Breathe-V study, a placebo-controlled randomized trial on 54 patients with Eisenmenger syndrome, showed a steady decrease in exercise capacity in patients with PAH associated with CHD when treated with placebo for 4 months.1 As a consequence, stabilization of exercise capacity can be considered an important gain in the treatment of PAH, also in patients with PAH associated with CHD.

Additionally, we demonstrated that stabilization of exercise capacity was accompanied by a statistically significant and sustained improvement of QoL. The 8 domains of the SF-36

Table 3. Cardiovascular Magnetic Resonance Imaging during follow-up (n=9)

Baseline Follow-up p

Left ventricle

End diastolic volume (ml) 140 ± 48 147 ± 46 0,4

End systolic volume (ml) 60 ± 31 62 ± 26 0,8

Stroke volume (ml) 78 ± 26 86 ± 23 0,3

Ejection fraction (%) 57 ± 11 59 ± 7 0,4

Right ventricle

End diastolic volume (ml) 166 ± 73 176 ± 68 0,4

End systolic volume (ml) 90 ± 48 90 ± 51 0,99

Stroke volume (ml) 76 ± 34 86 ± 21 0,2

Ejection fraction (%) 47 ± 12 52 ± 11 0,2

Mean values with SD. P-values compared to baseline.

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were evaluated separately. Although some QoL domains remained stable during treatment, others improved significantly. Role physical increased significantly during bosentan treatment, indicating that patients experienced less problems at work and during daily activities after 18 months of treatment. Vitality improved as well during follow-up, indicating an increased sensation of energy. In accordance with our results, Keogh et al showed similar results in patients with idiopathic PAH or PAH associated with connective tissue diseases during bosentan treatment.5 In patients with PAH, health related QoL is significantly impaired and the evaluation of QoL is of great importance. 21, 22 Moreover, from the patients’ perspective, QoL is one of the most important measures of treatment effect. Therefore, it is important to assess QoL as a major outcome parameter of treatment effect in patients with PAH.6

We also evaluated treatment effect in patients with Down syndrome. Little is known about the benefit of bosentan in patients with Down syndrome and PAH associated with CHD, while PAH is particularly common in these patients.23 In a previous small study, we reported a short-term increase in 6-MWD during bosentan treatment.14 Presently, in our larger population, this short-term improvement could not be confirmed. This could be due to the disputable validity of the 6-MWD in patients with Down syndrome, who have reduced mental capacity. Nonetheless, we chose to evaluate 6-MWD in these patients, as a more validated test to evaluate exercise capacity is presently lacking. Similarly, QoL questionnaires have not been properly validated in patients with Down syndrome, making their use for the evaluation of treatment effect questionable. To increase their validity, QoL questionnaires were filled in by the patients’ parents or guardians. In accordance with the 6-MWD, QoL scores remained unchanged during treatment, as did NT-pro-BNP levels.

The present study is limited by the lack of a placebo group and the heterogeneity of underlying diagnoses e.g. patients with and without the Down syndrome, patients with and without Eisenmenger syndrome, patients with and without closed defects and the variety of defects. Moreover, the 6-MWD is frequently used to evaluate treatment effect in PAH patients although the validity of this endpoint to reflect treatment effect is questionable. Other end points should be validated for the adequate evaluation of treatment effect. In the absence of an ideal endpoint, data on QoL, imaging of the right ventricle and the pulmonary vessels, and chemical markers of PAH should be used in parallel and compared with the 6-MWD in patients with and without Down syndrome.6 Therefore, definite conclusions on long-term treatment effects of bosentan cannot yet be made. In conclusion, our findings suggest that in patients without the Down syndrome longer-term bosentan treatment resulted in a persistent improvement of QoL and a stabilization of exercise capacity.

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5 Keogh AM, McNeil KD, Wlodarczyk J, Gabbay E, Williams TJ. Quality of life in pulmonary arterial hypertension: improvement and maintenance with bosentan. J Heart Lung Transplant 2007;26:181-7.

6 Peacock A, Naeije R, Galie N, Reeves JT. End points in pulmonary arterial hypertension: the way forward. Eur Respir J 2004;23:947-53.

7 Diller GP, Dimopoulos K, Kaya MG, Harries C, Uebing A, Li W, Koltsida E, Gibbs JS, Gatzoulis MA. Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease. Heart 2007;93:974-6.

8 Sitbon O, Beghetti M, Petit J, Iserin L, Humbert M, Gressin V, Simonneau G. Bosentan for the treat-ment of pulmonary arterial hypertension associated with congenital heart defects. Eur J Clin Invest 2006;36 Suppl 3:25-31.



11 Duffels M, van Loon L, Berger R, Boonstra A, Vonk-Noordergraaf A, Mulder B. Pulmonary arteri-al hypertension associated with a congenital heart defect: advanced medium-term medical treatment stabilizes clinical condition. Congenit Heart Dis 2007;2:242-9.


13 van Loon RL, Hoendermis ES, Duffels MG, Vonk-Noordegraaf A, Mulder BJ, Hillege HL, Berger RM. Long-term effect of bosentan in adults versus children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: does the beneficial effect persist? Am Heart J 2007;154:776-82.

14 Duffels MG, Vis JC, van Loon RL, Berger RM, Hoendermis ES, van Dijk AP, Bouma BJ, Mulder BJ. Down patients with Eisenmenger syndrome: Is bosentan treatment an option? Int J Cardiol 2008. Epub ahead of print.

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apacity and Q

uality of Life


15 ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003;167:211-77.

16 ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-7.

17 Galie N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T, Espinola-Zavaleta N, Rocchi G, Manes A, Frantz R, Kurzyna M, Nagueh SF, Barst R, Channick R, Dujardin K, Kronenberg A, Lecon-te I, Rainisio M, Rubin L. Effects of the oral endothelin-receptor antagonist bosentan on echocardi-ographic and doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:1380-6.

18 Meluzin J, Spinarova L, Bakala J, Toman J, Krejci J, Hude P, Kara T, Soucek M. Pulsed Doppler tissue imaging of the velocity of tricuspid annular systolic motion; a new, rapid, and non-invasive method of evaluating right ventricular systolic function. Eur Heart J 2001;22:340-8.

19 Huez S, Vachiery JL, Unger P, Brimioulle S, Naeije R. Tissue Doppler imaging evaluation of cardiac adaptation to severe pulmonary hypertension. Am J Cardiol 2007;100:1473-8.

20 Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hyper-tension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994;121:409-15.

21 McKenna SP, Doughty N, Meads DM, Doward LC, Pepke-Zaba J. The Cambridge Pulmonary Hyper-tension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension. Qual Life Res 2006;15:103-15.

22 Zlupko M, Harhay MO, Gallop R, Shin J, rcher-Chicko C, Patel R, Palevsky HI, Taichman DB. Evalu-ation of disease-specific health-related quality of life in patients with pulmonary arterial hypertension. Respir Med 2008.

23 Suzuki K, Yamaki S, Mimori S, Murakami Y, Mori K, Takahashi Y, Kikuchi T. Pulmonary vascular disease in Down’s syndrome with complete atrioventricular septal defect. Am J Cardiol 2000;86:434-7.

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88Chapter 8

Bosentan in patients with pulmonary arterial hypertension: A comparison between congenital heart disease and chronic pulmonary thromboembolism

Mariëlle GJ Duffels, Mart N van der Plas, Sulaiman Surie, Michiel M Winter, Berto J Bouma,

Maarten Groenink, Arie PJ van Dijk, Elke S Hoendermis, Rolf MF Berger, Paul Bresser,

Barbara JM Mulder.

Neth Heart Journal 2009; 9: 334-338.


AbstractBackground: In patients with pulmonary hypertension, it is unknown whether the treatment effect of bosentan is dependent on the duration of pulmonary vessel changes. Therefore, we studied the response on bosentan in patients with life-long pulmonary vessel changes (pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD)) and in patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension (CTEPH)).

Methods: In this open-label study, 18 patients with PAH due to CHD and 16 patients with CTEPH were treated with bosentan for at least 1 year. All patients were evaluated at baseline and during follow-up by means of the 6-minute walk distance (6-MWD) and laboratory tests.

Results: Improvement of 6-MWD was comparable in patients with PAH due to CHD (444 ± 112 m to 471 ± 100 m, p=0.02), and in CTEPH (376 ± 152 m to 423 ± 141 m, p=0.03) after 3 months of treatment. After this improvement, 6-MWD stabilized in both groups.

Conclusion: Although duration of pulmonary vessel changes is strikingly different in patients with PAH due to CHD and CTEPH, treatment effect of one year of bosentan treatment was comparable. The main treatment effect appears disease stabilization and decreasing the rate of deterioration.

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IntroductionPulmonary hypertension is a progressive disease, ultimately leading to right ventricular failure and death.1-3 Pulmonary hypertension may develop in patients with congenital heart disease (CHD), and in patients with chronic pulmonary thromboembolism.1 In CHD, approximately 6% of patients with a cardiac septal defect will develop pulmonary arterial hypertension (PAH), as a result of systemic-to-pulmonary shunting.4 Eventually, approximately 1% of CHD patients develop Eisenmenger syndrome in early childhood. Life expectancy of these patients is 20-50 years with an one year survival of 98%.4, 5

In patients with incomplete resolution of acute pulmonary thromboembolism, chronic thromboembolic pulmonary hypertension (CTEPH) may develop in adult life.6, 7 Although the chronic embolic material can be surgically removed by pulmonary endarterectomy,8 about 10% of patients who have undergone surgery will develop residual pulmonary hypertension.9 Moreover, about 50% of the CTEPH patients is assumed to be inoperable due to the distal location of the chronic thromboembolism.8, 10 Without treatment, survival rate is low and proportionate to the severity of disease, with an estimated one year survival of 40% in patients with mean pulmonary arterial pressure exceeding 50 mmHg.3

Treatment with bosentan, a dual endothelin receptor antagonist, has been reported to improve exercise capacity, and survival of patients with various forms of pulmonary hypertension, including both PAH due to CHD and inoperable CTEPH.10-15 However, since the duration of disease differs strikingly between both groups of patients, we hypothesized that the extent of the response to bosentan would differ. Until now, the treatment effect of bosentan in patients with a different duration of pulmonary vessel changes is unknown. We hypothesized that pulmonary vessel changes in patients with CTEPH have a more reversible character, due to shorter existence. Therefore, our hypothesis is that patients with CTEPH are more likely to respond positively on treatment with Bosentan. To evaluate this influence we compared the one year bosentan treatment effect in adult patients with life-long pulmonary vessel changes (PAH due to CHD) to adult patients with subacutely induced pulmonary vessel changes (CTEPH)).

Methods

Study population

For the present study, we retrospectively selected adult patients with PAH due to CHD and adult patients with CTEPH, who are being treated with bosentan for at least one year. Patients with Down syndrome, with obstructions of the right ventricular outflow tract, pulmonary valve or pulmonary arteries, and patients receiving prostacyclin, glibenclamide or cyclosporin treatment were excluded. Among CHD patients, PAH diagnosis was established, by echocardiography using tricuspid regurgitation jet velocity and right arterial pressure (systolic pulmonary arterial pressure (sPAP) > 40 mmHg).16 The Eisenmenger syndrome

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was defined as a congenital heart defect with a pulmonary-to-systemic shunt, observed by echocardiography. The diagnosis CTEPH was based on pulmonary angiography and right heart catheterization (mean pulmonary arterial pressure (mPAP) greater than 25 mmHg). To compare pulmonary arterial pressure between patients with PAH due to CHD and patients with CTEPH, we used sPAP estimated by echocardiography. All echocardiographic images were acquired and recorded digitally, and analyzed offline by a single observer. The protocol was approved by the institutional review committee.

Study protocol

This was an open-label study. All patients were evaluated at baseline and during follow-up by 6-minute walk test (6-MWT). The 6-MWT was performed according to the guidelines of the American Thoracic Society as described before, with continuous pulse oximetry monitoring and was used to establish the treatment response.17 To exclude the potential effect of a learning curve, the 6-MWT at baseline was performed twice, and the second 6-minute walk distance (6-MWD) was used as the baseline value. In addition, liver function, serum hemoglobin levels and serum NT-pro-BNP levels were monitored. NT-proBNP analysis was performed on a Modular E170 bench top analyser utilising a chemiluminescent assay with a coefficient of variation < 5% (Roche Diagnostics, Lewes, UK).

Oral bosentan was initiated at 62.5 mg twice daily. Four weeks later, bosentan was increased to a maximum dose of 125 mg twice daily, if well tolerated. Treatment safety was evaluated during follow-up by monitoring flushing and nasal congestion, vital signs, pulse oximetry, and premature treatment discontinuation. Liver function tests and hemoglobin levels were checked every 2 weeks for the first 2 months and monthly thereafter. According to the bosentan summary of product characteristics, the standard threshold for liver function abnormality of > 3 times upper limit of normal was applied.


The descriptive data are presented as mean with standard deviation if normally distributed or as median with range as appropriate. Changes from baseline to three months and one year are evaluated with a paired t test for continuous variables (and with Wilcoxon’s rank sum test for categorical variables). A value of p < 0.05 was considered to be significant.

Results

Study population

Between September 2003 and September 2006, 36 eligible patients started oral bosentan treatment. Induction of bosentan therapy was well tolerated within both patient groups. In addition, in patients with PAH due to CHD, we could not observe a decrease in oxygen

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saturation during bosentan treatment. During follow-up, one CTEPH patient withdrew from treatment because of severe liver function abnormalities. Another CTEPH patient had co-morbidity (rheumatoid arthritis) and could therefore not perform a 6-MWT after one year bosentan treatment. Consequently, results of 34 patients are presented.


Table 1 shows baseline characteristics of 34 patients (38% males, mean age 54, range 23- 86 years). Eighteen (53%) patients were diagnosed with PAH due to CHD and 16 (47%) patients were diagnosed with CTEPH. Underlying diagnoses of the CHD patients were ventricular septal defect (n=8), atrial septal defect (n=6), univentricular heart (n=2), patent ductus arteriosus (n=1) and transposition of the great arteries (n=1). Of the CHD patients, 4 patients had persistent PAH after previous device closure of their septal defect, 13 patients (72%) had Eisenmenger syndrome, and one patient with transposition of the great arteries had persistent pulmonary hypertension after Mustard correction. Among the CTEPH patients, 11 patients had distal, inoperable CTEPH and 5 patients had residual pulmonary hypertension diagnosed 6 to 27 months after pulmonary endarterectomy.

Table 1. Baseline characteristics

Total (n=34) CHD (n=18) CTEPH (n=16) P

Age (years) 54 (23- 86) 46 (23-73) 63 (35-86) 0.003

Male (%) 13 (38) 5 (28) 8 (50) 0.2

Eisenmenger syndrome (%) 11 (32) 11 (61)

6-MWD, mean ± SD (m.) 414 ± 133 444 ± 112 376 ± 152 0.2

Oxygen saturation, mean ± SD (%) 90 ± 8 86 ± 9 95 ± 4 0.002

NT-pro-BNP, median, range (ug/L) 466 (97 -9693) 460 (97-5815) 1126 (99-9693) 0.5

sPAP, mean ± SD (mmHg) 80 ± 19 85 ± 21 77 ± 18 0.3

CHD: pulmonary arterial hypertension due to congenital heart disease; CTEPH: chronic thromboembolic pulmonary hypertension; 6-MWD: six-minute walk distance; sPAP: systolic pulmonary arterial pressure

The CHD patients were significantly younger (46 years, range 23-73 years vs. 63 years, 35-86 years, p<0.01) and had a lower oxygen saturation (86 ± 9% vs. 95 ± 4%, p<0.01) compared to the CTEPH patients.

Exercise capacity

All included patients were treated with bosentan for at least one year (median follow-up 1.9 years, range 1.3- 4 years). During the first 3 months of treatment, mean 6-MWD improved significantly with 36 ± 53 m (from 414 ± 133 m to 450 ± 120 m, p<0.01), after which mean 6-MWD appeared to stabilize during the following 9 months. Compared to baseline a persistent, but small increase of 19 ± 56 m (p=0.06) remained after one year of treatment.

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In CHD patients, mean 6-MWD increased from 444 ± 112 m at baseline to 471 ± 100 m (p=0.02) after 3 months of bosentan treatment. During the following 9 months of treatment, 6-MWD gradually returned to baseline values. After one year of treatment, a slight increase of 6-MWD remained (14 ± 47 m; p=0.2) compared to baseline.

Mean 6-MWD in CTEPH patients increased during the first 3 months of treatment from 376 ± 152 m at baseline to 423 ± 141 m (p=0.03). As in CHD patients, after one year of treatment only a slight increase in 6-MWD (24 ± 65 m; p=0.2) remained in patients with CTEPH (figure 1). No correlation was found between time after pulmonary endarterectomy and observed changes in 6-MWD during follow-up (r=0.4, p=0.5).

Although the extent of response after 3 months of bosentan treatment seemed more pronounced in CTEPH patients, treatment effect was statistically comparable (p=0.3) in CHD and CTEPH patients. After one year bosentan treatment, mean 6-MWD had gradually returned to baseline values in both patients with PAH due to CHD as well as CTEPH patients, with a slight but persistent and comparable increase remaining of 14 ± 47 m and 24 ± 65 m (p=0.6), respectively. No correlations were found between the effect size of treatment and any of the baseline parameters in both patient groups.

Figure 1 shows the mean 6-minute walk distance (6-MWD) during one year of bosentan treatment among patients with pulmonary arterial hypertension due to congenital heart disease (CHD) and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In both patient groups, the greatest magnitude of improvement is shown during the first three months. After one year bosentan treatment, 6-MWD tends to stabilize.

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NT-pro-BNP

Median NT-pro-BNP was elevated at baseline in patients with PAH due to CHD and in patients with CTEPH (460 ng/L, range 97- 5815 ng/L vs. 1126 ng/L, range 99- 9693 ng/L; p=0.5). After one year of treatment, median NT-pro-BNP remained unchanged in both patient groups compared to baseline. Changes in NT-pro-BNP during treatment were not related to 6-MWD.

DiscussionAlthough pulmonary vessel changes exist much longer in patients with PAH due to CHD compared to patients with CTEPH, no differences were observed in treatment effect between both groups. During the first three months of treatment, mean 6-MWD improved significantly, after which 6-MWD appeared to stabilize during one year follow-up.

The observed initial improvement in exercise capacity is in agreement with previously reported results.10, 13, 15, 18-21 However, inconsistent data have been reported on treatment response after one year follow-up. Several studies in PAH due to CHD reported a persistent beneficial effect of bosentan on exercise capacity during longer term follow-up.12, 14, 22 In contrast, Apostolopoulou et al., reported a gradual return to baseline of exercise capacity after two years bosentan treatment in patients with PAH due to CHD.11 In a previous study in our institution among patients with PAH due to CHD, we demonstrated similar findings. Bosentan treatment resulted in short-term improvement in both adults and children with PAH associated with systemic-to-pulmonary shunt. At long-term follow-up, however, a gradual decline of the beneficial effect of bosentan was observed. The decline appeared to be particularly pronounced in paediatric patients, who in this study, tended to have more severe disease at baseline.23 In CTEPH, however, one open-label multicenter study demonstrated a sustained effect on 6-MWD after one year of treatment with bosentan.24

Stabilization of exercise capacity after one year of bosentan treatment could be considered beneficial. Unfortunately, therapeutic options are still limited and treatment is aimed to increase time to clinical worsening. In CTEPH patients, disease stabilization is more valuable compared to patients with PAH due to CHD as survival of untreated CTEPH patients remains poor, with an estimated one year survival of 40% in patients with a mPAP exceeding 50 mmHg. In contrast patients with PAH due to CHD are known to remain stable for several years without treatment.3, 5 This difference in prognosis could be due to a better preserved right ventricular function in patients with PAH due to CHD. In these patients, the right ventricle has been subjected to high pressures from early childhood.25 As a consequence, the right ventricle of patients with a cardiac septal defect may be better adjusted to support systemic pulmonary pressures compared to structurally normal hearts.26

The relatively worse cardiac status of the CTEPH patients could have been a reason for the observed lower exercise capacity in CTEPH patients at baseline and during follow-up.

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Moreover, the older age of CTEPH patients could also have played a role, as 6-MWD is known to decrease with age.27

Taking the decreased prognosis into consideration disease stabilization could be considered a more favourable response in CTEPH patients compared to patients with PAH due to CHD, as we hypothesized that, in view of the shorter duration of pulmonary vessel changes, reversibility of the pathological process was more likely in these patients. However, the duration of the vascular changes did not appear to be of influence on the extent and dynamics of response on bosentan treatment. Patients with life-long pulmonary vessel changes (PAH due to CHD) and patients with subacute pulmonary vessel changes (CTEPH) showed a comparable treatment response. A possible explanation for this comparable treatment response could be found in similar pathologic changes of the pulmonary microvasculature and marked endothelial dysfunction in both diseases.1, 28 Another explanation might be that more extensive improvements of vascular changes in the CTEPH patients are masked by right ventricular dysfunction. A direct effect of bosentan on the right ventricle is still subject to investigation.

In addition, in patients with PH, health related quality of life is significantly impaired and from the patients’ perspective, quality of life is one of the most important measures of treatment effect.29 Therefore, quality of life should be also assessed in the future as outcome parameter of treatment effect in patients with PAH.

Study limitations

Limitations of this study include the lack of a placebo group and the heterogeneity of the subgroups. Due to the relatively small sample size, analyses in subpopulations could not be performed. Moreover, in both groups, the exact duration of pulmonary vessel changes is unknown and data on the natural course of 6-MWD are lacking. In addition, right heart catheterization data were unavailable in patients with PAH due to CHD and follow-up data were incomplete for patients with CTEPH. As a result, we could not observe changes in hemodynamics over time. Prospective studies with larger numbers and longer follow-up duration are warranted.

Conclusion The extent and dynamics of response to one year bosentan treatment was comparable in patients with PAH due to CHD and patients with CTEPH. Differences in pulmonary vessel change duration between both groups did not influence treatment effect. Although treatment effect seems to be mainly one of disease stabilization and decreasing the rate of deterioration, this could be considered an advantage in these patients with decreased prognosis.

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Reference List 1 Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich

R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S.

2 Engelfriet PM, Duffels MG, Moller T, Boersma E, Tijssen JG, Thaulow E, Gatzoulis MA, Mulder BJ. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007;93:682-7.

3 Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up of patients with pulmonary throm-boembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151-8.


5 Oya H, Nagaya N, Uematsu M, Satoh T, Sakamaki F, Kyotani S, Sato N, Nakanishi N, Miyatake K. Poor prognosis and related factors in adults with Eisenmenger syndrome. Am Heart J 2002;143:739-44.

6 Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345:1465-72.

7 Pengo V, Lensing AW- Prins M, Prins MH - Marchiori A, Marchiori A, avidson BL - Tiozzo F, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S - Prandoni P, Prandoni P. Incidence of chronic thromboem-bolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-64.

8 Bresser P, Pepke-Zaba J, Jais X, Humbert M, Hoeper MM. Medical therapies for chronic thromboem-bolic pulmonary hypertension: an evolving treatment paradigm. Proc Am Thorac Soc 2006;3:594-600.

9 Auger WR, Kerr KM, Kim NH, Ben-Yehuda O, Knowlton KU, Fedullo PF. Chronic thromboembolic pulmonary hypertension. Cardiol Clin 2004;22:453-66, vii.

10 Bonderman D, Nowotny R, Skoro-Sajer N, Jakowitsch J, Adlbrecht C, Klepetko W, Lang IM. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2599-603.



13 Hoeper MM, Kramm T, Wilkens H, Schulze C, Schafers HJ, Welte T, Mayer E. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2363-7.

14 Gatzoulis MA, Beghetti M, Galie N, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M. Long-er-term bosentan therapy improves functional capacity in Eisenmenger syndrome: Results of the BREATHE-5 open-label extension study. Int J Cardiol 2007;127:27-32.


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18 Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Effect of the oral endothelin antagonist bosentan on the clinical, exercise, and haemodynamic status of patients with pulmonary arterial hyper-tension related to congenital heart disease. Heart 2005;91:1447-52.


20 Duffels M, van Loon L, Berger R, Boonstra A, Vonk-Noordergraaf A, Mulder B. Pulmonary arteri-al hypertension associated with a congenital heart defect: advanced medium-term medical treatment stabilizes clinical condition. Congenit Heart Dis 2007;2:242-9.

21 Seyfarth HJ, Hammerschmidt S, Pankau H, Winkler J, Wirtz H. Long-term bosentan in chronic throm-boembolic pulmonary hypertension. Respiration 2007;74:287-92.



24 Hughes RJ, Jais X, Bonderman D, Suntharalingam J, Humbert M, Lang I, Simonneau G, Pepke-Zaba J. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study. Eur Respir J 2006;28:138-43.

25 McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G. Progno-sis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:78S-92S.

26 Hopkins WE, Waggoner AD. Severe pulmonary hypertension without right ventricular failure: the unique hearts of patients with Eisenmenger syndrome. Am J Cardiol 2002;89:34-8.

27 Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med 1998;158:1384-7.

28 Ulrich S, Fischler M, Speich R, Popov V, Maggiorini M. Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties. Chest 2006;130:841-6.

29 Cenedese E, Speich R, Dorschner L, Ulrich S, Maggiorini M, Jenni R, Fischler M. Measurement of qual-ity of life in pulmonary hypertension and its significance. Eur Respir J 2006;28:808-15.

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99Chapter 9

Why six-minute walk test is not an appropriate endpoint in mildly symptomatic pulmonary hypertension patients

Mart N van der Plas, Mariëlle GJ Duffels, Dikyi Ponse, Reindert P van Steenwijk,

Barbara JM Mulder, Paul Bresser.

Based on correspondence to the Lancet 2008; 372: 1730.


IntroductionIn pulmonary hypertension (PH), the six-minute walk test (6MWT) is frequently used as primary endpoint of clinical trials. The six-minute walk distance (6MWD) is considered to reflect decreased maximal aerobic capacity due to the inability of the heart to sufficiently increase pulmonary blood flow, by increased pulmonary arterial pressure.1, 2 This assumption holds for severely impaired PH patients (NYHA III and IV) where changes in 6MWD are directly related to changes in hemodynamic severity of disease. In mildly impaired patients, however, obvious improvements in hemodynamics were reported to be accompanied by either no, or less markedly improvements in 6MWD.3, 4 This discrepancy has been attributed to the so called ceiling effect, i.e. the point at which performance is so good that further significant improvement becomes hard to detect. For mildly impaired PH patients this may mean that the 6MWT is just not demanding enough to evoke maximal aerobic capacity and corresponding maximal cardiac output. We hypothesized that the 6MWT does not reflect maximal aerobic capacity in mildly impaired PH patients. Therefore, we studied aerobic capacity during both the 6MWT and an incremental cardio pulmonary exercise test (CPET) on a bicycle ergometer, in severely and mildly impaired PH patients, as well as healthy control subjects. The results of this study might have implication for the usefulness of the 6MWT in clinical trials.

Methods

Subjects

This study included 21 adult patients with PH (NYHA II (n=8) and NYHA III (n=13)), associated with either congenital heart disease (CHD) (n=8) or associated with chronic thromboembolism (n=13), as well as 8 age and sex matched healthy controls. The diagnosis chronic thromboembolic pulmonary hypertension (CTEPH) was based on pulmonary angiography, ventilation perfusion scanning and by means of right heart catheterization (mean pulmonary arterial pressure > 25 mmHg).5 PAH due to congenital heart disease was established by echocardiography by means of the tricuspid regurgitation jet velocity (systolic pulmonary arterial pressure > 40 mmHg). Patients with Down syndrome were excluded in this study. The research protocol was approved by the local institutional review board, and the study was carried out in accordance with the principles of the declaration of Helsinki.

Study design

This was a prospective 3-group cross-sectional study. 6MWT and CPET were performed within 1 week. In case both tests were done at the same day, it was reasoned that the CPET had to be performed at least 60 minutes after the 6MWT so ventilation and hemodynamics could return to baseline.

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6MWTThe 6MWT was performed according to the guidelines of the American Thoracic Society (ATS).6 At least one practice walk test was performed. Patients were instructed to walk at their own pace, along a 40 meter corridor and to cover as much ground as possible in 6 minutes. During the test patients were encouraged with standard phrases every minute, as stated in the ATS protocol. Patients were allowed to stop during the test, but were instructed to resume walking as soon as they felt possible. Dyspnea was evaluated with the Borg dyspnea scale at the beginning and end of the test.

During the 6MWT oxygen uptake (V’O2), carbon dioxide production (V’CO2), minute ventilation (V’E) and heart rate (HR) were measured using a portable telemetric system (Cosmed K4b2; Cosmed, Rome, Italy). Oxygen pulse (O2-pulse), as a derivative of stroke volume, was calculated as the result of V’O2/HR. The breathing equivalent for CO2 (EqCO2) was calculated as V’E/V’CO2. Oxygen saturation (SpO2) was measured using a telemetric transcutaneous pulse oximeter (Nonin 8500 M, Nonin Medical, Minneapolis USA).

CPET

The symptom limited CPET was performed according to the guidelines of the American Thoracic Society.7 Briefly, patients were placed on a cycle ergometer in the upright position and continuous breath-by-breath measurements were made of V’E, V’O2, V’CO2, HR, O2-pulse, blood pressure and electrocardiography. Work load was increased by 5 to 15 Watt, depending on the predicted maximum exercise capacity and in such a way that maximal effort was attained within 10-15 minutes.

Statistics

All results are expressed as mean±SD. Analyses were performed with the SPSS statistical package (SPSS 13.0; Chicago, IL). The Jonckheere–Terpstra test was used to analyze the trend between the aerobic capacity (continuous variable) and NYHA functional class (discontinuous variable).8 The differences between groups were tested with a parametric 1-way analysis of variance. In case of an overall statistical difference, the differences between 2 groups were further analyzed with the Student t test. Moreover, a paired Student t-test was used to analyse the differences in cardio/ventilatory responses to both 6MWT and CPET.

ResultsBaseline characteristics for the patients with PH, both mild and more severe, as well as for the control subjects are summarized in table 1. Systolic pulmonary arterial pressure (sPAP), measured with trans-thoracic echocardiography, was significantly higher in the more severely impaired patients compared with the mildly impaired patients. Although it was not measured, sPAP was considered normal in the healthy control subjects. There was no significant difference

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in age, height or weight and other resting parameters between the mildly and more severely impaired PH patients, although there was a significant predominance of females in the NYHA III group (11 vs. 2 in the NYHA II group; Pearson Chi-Square p<0.01). The total PH group did not differ from the group with healthy controls, except for resting oxygen saturation (90±6% vs. 97±1%; p<0.01).

Table 1. baseline characteristics

Controls NYHA II NYHA III

Subjects, n 8 8 13

CTEPH/CHD, n 6/2 7/6

Demographics

Age, yrs 41±13 54±12 45±10

Female/male, n 4-apr 2/6 11/2X

Weight, kg 71±11 72±13 73±19

Height, cm 176±9 169±11 167±8

Resting parameters

sPAP, mmHg 71±15 88±14

HR, beats.min-1 77±15 71±16 76±12

V’O2, ml.min-1 342±85 285±95 309±102

SpO2, % 97±1 93±4* 90±6*

Definition of abbreviations: CTEPH = chronic thromboembolic pulmonary hypertension; CHD = congenital heart disease; sPAP = systolic pulmonary arterial pressure; HR = heart rate; V’O2 = oxygen consumption; SpO2 = transcutaneous oxygen saturation. x significant difference between NYHA II and NYHA III * significant difference between PH patients and healthy controls

Physiological responses to the 6MWT

In the group with PH patients, there was no significant difference in 6MWD with portable telemetric measurements (476±102) and the a priori performed 6MWT without (487±90). There was, however, a significant increase in both 6MWD and the cardio/ventilatory responses to 6MWT with decreased disease severity (table 2). 6MWD decreased with increasing severity of disease, as did the corresponding oxygen uptake (V’O2). For both EqCO2 and O2-pulse the Jonckheere–Terpstra test was significant (both p <0.01), indicating a significant increase in EqCO2 and decrease in O2-pulse with increased disease severity. The additional Student t test, however, only showed a significantly difference between the healthy control subjects and PH patients, but not among the PH patients. V’E and HR did not significantly differ among the groups.

Physiological responses to CPET

Physiological responses to CPET for both the patients with PH and the control subjects are also summarized in table 2. Maximal power output was significantly higher with decreased severity of disease, as was the corresponding V’O2, V’E, HR and O2-pulse. EqCO2 was significantly

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higher in the group of PH patients, compared to the healthy control subjects, but did not differ between the NYHA II and NYHA III PH patients.

Tabel 2. Physiologic responses exercise

Controls NYHA II NYHA III

6MWT

Distance, m 739±73 563±68 a 423±82 b

V’O2, ml.min-1 2115±266 1376±397 a 1007±336 b

V’E, l.min-1 62.4±13.9 59.2±19.7 48.8±15.2

HR, min-1 149±21 134±24 126±24

EqCO2 30.8±4.4 49.3±11.2 a 56.3±11.6

O2-pulse, ml 15.0±2.6 10.6±2.9 a 8.4±2.6

RER 0.92±0.09 0.84±0.11 0.80±0.06

CPET

Load, Watt 236±65 128±42 a 63±18 b

V’O2, ml.min-1 2853±713 1632±456 a 993±343 b

V’E, l.min-1 115.2±26.3 85.7±25.5 a 55.2±18.6 b

HR, min-1 174±14 154±10 a 132±27 b

EqCO2 26.7±4.1 45.4±7.5 a 46.7±11.0

O2-pulse, ml 16.5±4.3 10.7±3.2 a 7.7±2.5 b

RER 1.14±0.07 0.98±0.04 a 0.95±0.07

Difference (CPET-6MWT)

V’O2, ml.min-1 737±618 + 257±231 a+ -14±148 b

V’E, l.min-1 52.8±26.4 + 26.4±17.2 a+ 6.4±10.4 b+

HR, min-1 25±12 + 20±18 + 6±16

EqCO2 4.0±4.7 + 3.2±7.2 0.3±8.6

O2-pulse, ml 1.5±2.9 0.1±1.7 -0.7±0.8 +

RER 0.22±0.13 + 0.15±0.09 + 0.15±0.10 +

Definition of abbreviations: V’O2 = oxygen consumption; V’E = minute ventilation; HR = heart rate; EqCO2 = breathing equivalent for CO2 (V’E/V’CO2); O2-pulse = oxygen pulse (V’O2/HR); RER = respiratory exchange ratio (V’O2/V’CO2), a significant difference between healthy control group and group with NYHA II PH patients. b significant difference between group with NYHA II PH patients and group with NYHA III PH patients, + significant difference between CPET and 6MWT

Comparison CPET and 6MWT

The differences in physiological responses to CPET and 6MWT of all three groups are presented in table 2. In both the group of healthy control subjects as the group of NYHA II PH patients, the V’O2, V’E, HR and RER were significantly higher during CPET than during 6MWT. In the NYHA III PH group, however, no significant difference was found in V’O2 and HR between CPET and 6MWT, although V’E and RER were significant higher and the O2-pulse was significant lower during CPET.

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The difference in V’O2 and V’E increased with decreasing severity of disease (figure 1). Although the Jonckheere–Terpstra test showed a significant trend for the difference in HR, EqCO2 and O2-pulse no significant differences between the successive groups were found with the additional Student t test.

Figure 1. Difference in peak oxygen consumption (V’O2-peak) between cardio pulmonary exercise testing (CPET) and the six-minute walking test (6MWT) against severity of disease.

DiscussionIn this study we assessed aerobic capacity during the 6MWT in severely and mildly impaired PH patients, as well as healthy control subjects. In line with our hypothesis, we reported increasing difference between maximal aerobic capacity and the aerobic capacity attained during 6MWT, with decreasing severity of disease. In mildly impaired PH patients, the 6MWT did not reflect maximal aerobic capacity. The 6MWD might therefore not be the most appropriate parameter of outcome in this group.

Although designed to assess the sub maximal level of functional capacity6, the 6MWT is considered to reflect decreased maximal aerobic capacity in patients with PH.9, 10 In the current study, 6MWT indeed required maximal attainable aerobic capacity, however, only in the more severely impaired PH patients. This observation is partly in concurrence with an earlier report by Deboeck and co-workers.9 They reported patients with pulmonary arterial hypertension to exercise at higher aerobic capacity but lower metabolic stress during the 6MWT than during a CPET.9 Surprisingly, the majority of their patients were in NYHA functional class I or II, with only a smaller part in NYHA functional class III. However, in their total analysis, no further division was made between the different functional class groups.

The mildly impaired patients (NYHA II) in our study, as well as our healthy control subjects, on the other hand, showed an increased difference between aerobic capacity measured during 6MWT and CPET, as V’O2-peak increases. This indicates that the NYHA II functional

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class PH patients are limited in their 6MWT for other reasons than their oxygen delivery capacity. It might, therefore, be questionable whether the 6MWD is the most appropriate parameter of outcome in this group, as has already been discussed by Frost and co-workers.11 They reported the existence of the so called “ceiling effect” when 6MWD was used as the endpoint in pulmonary arterial hypertension clinical trials. A ceiling effect is that point at which the performance is so good that further significant improvement becomes hard to detect. As the result of this ceiling effect, treatment effect was found to be lower when less severe (NYHA II) patients were enrolled in the study.11

With the use of the 6MWD as primary endpoint in clinical trials, the cause of the ceiling effect lies in increasing discrepancy between maximal aerobic capacity and aerobic capacity needed during 6MWT, with decreasing severity of disease. Since aerobic capacity and cardiac output are directly related, the inability of the heart to sufficiently increase pulmonary blood flow will result in decreased maximal aerobic capacity. When 6MWD is not limited by maximal aerobic capacity, further improvement of maximal aerobic capacity will not increase 6MWD. This may explain the findings of earlier studies where obvious improvements in hemodynamics were reported to be accompanied by either no, or less markedly improvements in 6MWD.3, 4 At the same time, the absence of improvement in 6MWD may not exclude an improvement in maximal aerobe capacity. Other parameters may be needed to evaluated changes in maximal aerobic capacity in mildly impaired PH patients.

Although the presented results might have implication for the usefulness of the 6MWT in clinical trials, there are some considerations that have to been taken into account. Firstly the relatively small number of patients. The distinctness of the results, however, may indicate that the results will only be confirmed by larger numbers. Secondly, the homogeneity of the studied group needs to be taken into consideration. However, although only PH patients associated with either congenital heart disease or chronic thromboembolism were studied, there are no reasons to believe that the found mechanisms may differ in other groups of PH patients.

ConclusionIn mildly impaired PH patients, the 6MWT is not demanding enough to evoke maximal aerobic capacity. These observations indicate that the 6MWD may not be an appropriate parameter of outcome in mildly impaired PH patients. The absence of improvement in 6MWD does not exclude an improvement in maximal aerobe capacity in these mildly symptomatic PH patients.

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Reference List 1 Holverda S, Gan CT, Marcus JT, Postmus PE, Boonstra A, Vonk-Noordegraaf A. Impaired stroke

volume response to exercise in pulmonary arterial hypertension. J Am Coll Cardiol 2006;47:1732-3.

2 Raeside DA, Smith A, Brown A, Patel KR, Madhok R, Cleland J, Peacock AJ. Pulmonary artery pressure measurement during exercise testing in patients with suspected pulmonary hypertension. Eur Respir J 2000;16:282-7.

3 Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR. Sitaxsentan therapy for pulmonary arterial hyperten-sion. Am J Respir Crit Care Med 2004;169:441-7.

4 Galie N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi E, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371:2093-100.



7 Ross RM ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003;167:1451.

8 Mahrer JM, Magel RC. A comparison of tests for the k-sample, non-decreasing alternative. Stat Med 1995;14:863-71.

9 Deboeck G, Niset G, Vachiery JL, Moraine JJ, Naeije R. Physiological response to the six-minute walk test in pulmonary arterial hypertension. Eur Respir J 2005;26:667-72.

10 Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hyper-tension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000;161:487-92.

11 Frost AE, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, Robbins IM, Shapiro S, Tapson VF, Zwicke D, DeMarco T, Schilz R, Rubenfire M, Barst RJ. The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect. Vascul Phar-macol 2005;43:36-9.

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1010Chapter 10

Duration of right ventricular contraction predicts the efficacy of bosentan treatment in patients with pulmonary hypertension

Mariëlle GJ Duffels, Maxim Hardziyenka, Sulaiman Surie, Rianne HACM de Bruin-Bon,

Elke S Hoendermis, Arie PJ van Dijk, Berto J Bouma, Hanno L Tan, Rolf MF Berger,

Paul Bresser, Barbara JM Mulder

Eur J Echocardiogr 2009; 10: 433-438.


AbstractAims In patients with pulmonary hypertension (PH), elevated endothelin-1 levels are associated with prolonged duration of right ventricular (RV) contraction, which induces leftward ventricular septal bowing with impaired left diastolic filling. We hypothesized that baseline RV contraction duration predicts efficacy of endothelin receptor antagonist, bosentan.

Methods and results Eighteen PH patients (age 57, range 35-79 years, 33% male) received bosentan. Six-minute walk distance (6-MWD) and echocardiography were performed at baseline and after 1 year follow-up. After 1 year of treatment, 6-MWD increased (mean 60 ± 41 m) in 67% of patients (responders). Baseline RV contraction duration was longer in responders, compared to non-responders (612 ± 66 ms vs. 514 ± 23 ms; p<0.01). A baseline RV contraction duration >550 ms was associated with improved 6-MWD (sensitivity 83%, specificity 83%; p<0.01).

Conclusion An improvement of 6-MWD during bosentan treatment was associated with a decrease in RV contraction duration and could be predicted by a baseline RV contraction duration >550 ms.

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IntroductionPulmonary hypertension (PH) is a progressive disease characterized by elevated endothelin-1 levels associated with vasoconstriction and structural changes in the pulmonary vascular bed.1, 2 In addition, it has been demonstrated that in patients with PH, the duration of right ventricular (RV) contraction3 is prolonged resulting in leftward ventricular septal bowing and impaired left ventricular (LV) early diastolic filling.4-6 Prolongation of RV contraction duration is associated with elevated endothelin-1 levels.7-9

Recently, it has been demonstrated that treatment with an endothelin receptor antagonist (bosentan) results in reverse remodelling of the pulmonary vascular wall leading to a decrease in pulmonary vascular resistance.10 Moreover, bosentan treatment resulted in a reduction of contraction duration leading to a reduction of leftward ventricular septal bowing and an improvement of LV early diastolic filling.11 Consequently, bosentan treatment improves haemodynamics, 6-minute walk distance (6-MWD) and survival in patients with various forms of PH.10, 12-20 The 6-MWD is frequently used in clinical practice to assess response to therapy in PH. As an intermediate end point, the distance walked may translate to the ability to perform activities of daily living, exercise capacity, and quality of life in PH patients.21 However, not all patients with PH show improvement of 6-MWD during treatment, and predictors for efficacy of bosentan treatment have not yet been identified.12, 16, 19, 22 Therefore, the present study was designed to test the following hypotheses: 1. RV contraction duration at baseline is a predictor of improvement in exercise capacity 2. RV contraction duration shortening during treatment is associated with an increase in exercise capacity.

Methods

Patients

In this retrospective open-label study, we analyzed adult patients with pulmonary arterial hypertension associated with congenital heart disease (n=9) and patients with chronic thromboembolic PH (n=9). Excluded were patients with Down syndrome, obstruction of the RV outflow tract, pulmonary valve or pulmonary arteries, or patients who were under treatment with prostacyclin, glibenclamide or cyclosporin. Patients were examined at baseline prior to treatment and re-examined after 1 year follow-up. A 12-leads surface ECG was recorded of all patients. In patients with congenital heart disease, pulmonary arterial hypertension was diagnosed by echocardiography (systolic pulmonary arterial pressure > 40 mm Hg).23 The diagnosis chronic thromboembolic PH was established with pulmonary angiography and right heart catheterization (mean pulmonary arterial pressure greater than 25 mm Hg).24 To compare pulmonary arterial pressure between patients with pulmonary arterial hypertension associated with congenital heart disease and patients with chronic thromboembolic PH, we used systolic pulmonary arterial pressure estimated by echocardiography.

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Exercise capacity

The 6-MWD was the primary end-point and was measured at baseline and after 1 year of bosentan treatment, according to the guidelines of the American Thoracic Society with continuous pulse oximetry.25 To avoid the effect of a learning-curve, the 6-MWD at baseline was measured twice, the second 6-MWD was used as baseline value in the analysis. Patients with an increase in 6-MWD during bosentan treatment were defined as responders.

Echocardiography

All patients underwent an echocardiographic examination at baseline and after 1 year follow-up. All echocardiographic images were acquired and recorded digitally, and analyzed offline. Parasternal and apical views were obtained according to the recommendations of the American Society of Echocardiography.26 Pulsed and color-coded Tissue Doppler Imaging recordings were obtained from an apical four-chamber view. All studies were analyzed by a single observer who was blinded to clinical information.

From the apical four-chamber view LV- and RV end-diastolic area11, tricuspid annular plane systolic excursion, and tricuspid regurgitation jet were analyzed. LV- and RV end-diastolic area were indexed by body surface area. Tricuspid annular plane systolic excursion was measured by M-mode at the junction of the RV free wall and tricuspid valve annular plane in the apical view. The peak velocity of the tricuspid regurgitation jet, was used to calculate systolic pulmonary arterial pressure.11 The RV fractional area change was calculated from the RV end-diastolic and end-systolic areas.11 Cardiac output was determined from pulsed-wave measurements of the LV outflow tract velocity profile and LV outflow tract diameter. The eccentricity index was obtained to determine the degree of leftward ventricular septal displacement, and was calculated as the perpendicular ratio of two short-axis diameters measured at early diastole.27 The minimum diameter of the inferior vena cava during respiration was measured from subcostal images.11

Tissue Doppler Imaging parameters were measured offline. Color-coded myocardial velocities were recorded with a 5-mm sample volume at the basal level of the RV free wall.

Figure 1. Measurement of right ventricular (RV) contraction duration. RV contraction duration using Tissue Doppler Imaging is measured as the time interval between onset of QRS and onset of RV early diastolic relaxation. Dotted arrow represents RV contraction duration.

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TEI-index28, LV- and RV early diastolic relaxation velocities 11 and LV- and RV contraction duration were analyzed. RV contraction duration was measured from the onset of the QRS complex to the onset of early diastolic filling of the RV (E), as shown in figure 1. RV contraction duration was corrected for heart rate.3

Treatment

Bosentan was initiated at a dose of 62.5 mg twice daily, which was doubled after 4 weeks unless elevated liver enzymes were observed. Liver enzymes, serum bilirubin and haemoglobin levels were monitored monthly. According to the bosentan summary of product characteristics, the standard threshold for liver function abnormality of > 3 times upper limit of normal was applied.


The descriptive data are presented as mean with standard deviation if normally distributed or as median with range as appropriate. Changes from baseline to 1 year were evaluated with a paired t test for continuous variables (and with Wilcoxon’s rank sum test for categorical variables). Comparisons between responders and non-responders were performed by independent samples t testing (2-tailed). Linear regression analysis was used to assess the relation between change in 6-MWD and age and echocardiographically measured parameters. Multivariate analysis of change in 6-MWD, age and RV contraction duration was used to assess contributing parameters. Receiver operating characteristics were constructed using any increase in 6-MWD as response variable. A value of p < 0.05 was considered to be significant.

Results


Eighteen patients (9 patients with pulmonary arterial hypertension associated with congenital heart disease and 9 patients with chronic thromboembolic PH) were treated with bosentan for at least 1 year. Table 1 shows baseline characteristics of these 18 patients (mean age 57 years, range 35 - 79 years, 33% males). Underlying diagnoses of the patients with pulmonary arterial hypertension associated with congenital heart disease were ventricular septal defect (n=5), atrial septal defect (n=3) and patent ductus arteriosus (n=1). Of these patients, 2 patients had persistent pulmonary arterial hypertension after previous device closure of their septal defect (a ventricular septal defect and an atrial septal defect, respectively), and 7 patients (78%) had the Eisenmenger syndrome. Among the chronic thromboembolic PH patients, 6 patients had distal, inoperable chronic thromboembolic PH and 3 patients had persistent PH, diagnosed 7 to 12 months after pulmonary endarterectomy.

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Effects of treatment

Induction of oral bosentan therapy was well tolerated, without signs of decreasing oxygen saturation. In 1 patient with pulmonary arterial hypertension associated with congenital heart disease an asymptomatic increase in liver transaminases (>3 times upper limit of normal) was observed which resolved within 2 weeks after dose reduction, whereupon the 125 mg twice daily dose was resumed without reoccurrence of the problems.

After 1 year bosentan treatment, 12 patients (67%) showed an improvement in 6-MWD (responders) by a mean of 60 ± 41 m whereas 6-MWD decreased in 6 patients (non-responders) by a mean of -24 ± 24 m. Among the responders, 7 patients had pulmonary arterial hypertension associated with congenital heart disease (mean increase 44 ± 19 m; p=0.001) and 5 patients had chronic thromboembolic PH (mean increase 83 ± 54 m; p=0.03). At baseline, responders were younger (mean age 52 ± 11 years vs. 68 ± 11 years; p=0.01) (table 1), had a higher mean systolic pulmonary arterial pressure (89 ± 21 mm Hg vs 64 ± 19 mm Hg; p=0.03) and had a longer RV contraction duration (612 ± 66 ms vs. 514 ± 23 ms; p<0.01) compared to non-responders, as shown in table 2.

Analyses of the RV tended to demonstrate on average a decrease in RV contraction duration after 1 year bosentan treatment in the responders from 612 ± 66 ms at baseline to 566 ± 77 ms (p=0.1). The minimum diameter of the inferior vena cava decreased significantly (p=0.03). Conversely, other echocardiographic measurements of the RV e.g. systolic pulmonary arterial pressure, RV fractional area change, tricuspid annular plane systolic excursion and TEI index

Table 1. Baseline characteristics

Total (n=18)

Responders (n=12)

Non-responders (n=6)

p Value

Age (years) 57 (35-79) 52 (35-73) 68 (55-79) 0.01

Gender, male, n (%) 6 (33) 3 (25) 3 (50) 0.3

CHD, n (%) 9 (50) 7 (78) 2 (22) 0.3

Eisenmenger syndrome, n (%) 6 (67) 5 (83) 1 (17) 0.3

CTEPH, n (%) 9 (50) 5 (56) 4(44) 0.3

Six-minute walk distance (m) 416 ± 116 430 ± 108 390 ± 136 0.5

Oxygen saturation (%) 89 ± 7 88 ± 9 92 ± 8 0.4

sPAP (mm Hg) 81 ± 23 89 ± 21 64 ± 19 0.03

NYHA classification

NYHA II, n (%) 2 (11) 1 (8) 1 (17) 0.6

NYHA III, n (%) 16 (89) 11 (92) 5 (83) 0.6

QRS (ms) 111 ± 21 110 ± 20 120 ± 20 0.5

QTc (ms) 404 ± 41 407 ± 40 398 ± 49 0.7

Data are presented as mean with stardard deviation if normally distributed or as median with range as appropriate. Comparisons among the responders and non-responders were performed using an independent t-test. CHD = congenital heart defect; CTEPH = chronic thromboembolic pulmonary hypertension; sPAP = systolic pulmonary arterial pressure; QRS = QRS duration; QTc = QTc duration.

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remained unchanged during follow-up in the responders. Analyses of the LV at baseline and after 1 year bosentan treatment showed a significant increase in LV end-diastolic area index in the responders from 11.0 ± 2 cm2/m2 to 12.2 ± 2 cm2/m2 (p=0.04), together with a significant increase of LV early diastolic relaxation velocity (from 6.7 ± 2 cm/s to 8.1 ± 2 cm/s; p=0.02). In table 2, echocardiographic parameters at baseline and after 1 year bosentan treatment are shown for all 18 patients.

Predictors of response

Using linear regression analyses, change in 6-MWD in all 18 PH patients was associated with age (R=0.5, p=0.04) and RV contraction duration at baseline (R=0.8, p<0.01). Moreover, change in 6-MWD was also associated with change in RV contraction duration (R= -0.6, p=0.02) and change in LV eccentricity index (R= -0.7, p=0.003) after 1 year of bosentan treatment. The other echocardiographically measured parameters at baseline had no contributing effect on change of 6-MWD. In multivariate analysis, RV contraction duration

Table 2. Echocardiographic parameters pre- and post bosentan treatment

Responders (n=12) Non responders (n=6)

Parameters Pre Post p Value Pre Post p Value

Left ventricle (LV)

LV ED area index (cm²/m²) 11.1 ± 2 12.2 ± 2,1 0.04 13.3 ± 2,3 13.1 ± 3.2 0.8

TVI LVOT index (cm/m²) 10.6 ± 3.6 11.1 ± 2.7 0.7 11.6 ± 2,1 13.7 ± 3.1 0.1

CI, LV (L/min/m²) 2.8 ± 0.9 3.0 ± 0.6 0.5 3.0 ± 0,8 3.8 ± 1.1 0.06

SV index (ml/m²) 33 ± 7 38 ± 12 0.2 39 ± 9 41 ± 13 0.6

LV E’ (cm/s) 6.7 ± 2 8.1 ± 2.0 0.02 6.6 ± 4 8.6 ± 3 0.05

LV contraction duration (ms) 571 ± 64 542 ± 45 0.4 503 ± 19 520 ± 60 0.6

Eccentricity index 2.1 ± 0.3 1.8 ± 0.3 0.07 1.6 ± 0,6 1.7 ± 0.7 0.9

Right ventricle (RV)

RV ED area index (cm²/m²) 13.5 ± 5 13.2 ± 4.0 0.6 11.4 ± 2 11.1 ± 3 0.6

TVI RVOT index (cm/m²) 6 ± 1.3 7.3 ± 1.4 0.001 7.3 ± 2,9 7 ± 1.5 0.6

RV E’ (cm/s) 5.9 ± 2 6.9 ± 2 0.1 4.5 ± 2 5.2 ± 3 0.7

RV contraction duration (ms) 612 ± 66 566 ± 77 0.1 514 ± 23 541 ± 68 0.5

sPAP (mm Hg) 89 ± 21 86 ± 23 0.7 64 ± 19 63 ± 22 0.8

TAPSE (mm) 19 ± 6 20 ± 5 0.5 16.9 ± 5 18.1 ± 8 0.6

TEI index 0.5 ± 0.1 0.5 ± 0.1 0.9 0.5 ± 0.1 0.5 ± 0.2 0.9

FAC 31.9 ± 11.4 31.6 ± 11.3 0.9 38 ± 12 38 ± 15.9 0.9

IVC minimum diameter (cm) 1.2 ± 0.5 0.8 ± 0.5 0.03 0.54 ± 0.4 0.8 ± 0.4 0.4

Data are presented as mean with standard deviations; ED = end diastolic; TVI = time velocity intergral; LVOT = left ventricular outflow tract; CO = cardiac output; SV = stroke volume; E’ = early diastolic filling; RVOT = right ventricular outflow tract; sPAP = systolic pulmonary arterial pressure; PVR = pulmonary vascular resistance; TAPSE = tricuspid annular plane systolic excursion; FAC = right ventricular fractional area change; IVC = inferior vena cava.

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at baseline remained an independent predictor for change in 6-MWD (Beta=0.9; p=0.04) (figure 2).

The optimal cut-off value of RV contraction duration at baseline to predict an increase of 6-MWD was 550 ms. In the receiver operating characteristics, we found an area under the curve of 0.92 (p=0.005) with a sensitivity of 83% and a specificity of 83%.

DiscussionIn the present study, we demonstrated that in patients with pulmonary arterial hypertension associated with congenital heart disease and in patients with chronic thromboembolic PH, the beneficial treatment effect of bosentan, i.e. the improvement of 6-MWD, was related with change in RV contraction duration. The main finding of the present study is that RV contraction duration at baseline is an independent predictor for response. A baseline RV contraction duration > 550 ms was associated with an improvement of exercise capacity after 1 year bosentan treatment.

In patients with PH, endothelin-1 levels are elevated.1, 2 Bosentan (an endothelin receptor antagonist) has been shown to counteract endothelin-1 induced vasoconstriction, cell proliferation and migration.1 Bosentan treatment may result in reverse remodelling of the pulmonary vascular wall leading to a decrease in pulmonary vascular resistance, a decline in RV end diastolic area index and an improvement of RV contractility. 1, 11, 29 In our study, improvement of 6-MWD was present in 67% of the patients. However, treatment resulted neither in a decline of RV end diastolic area index nor in an improved RV contractility (as assessed by RV fractional area change and tricuspid annular plane systolic excursion) nor in a decrease in systolic pulmonary arterial pressure. These results may suggest that beside

Figure 2. Relation between right ventricular (RV) contraction duration at baseline and change in 6-minute walk distance (6-MWD) after 1 year bosentan treatment, adjusted for age, change in RV contraction duration and change in LV eccentricity index. RV contraction duration at baseline is positively related with change in 6-MWD (R=0.9; p=0.04). RV = right ventricle.

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a decrease of RV pressure overload an additional mechanism might be responsible for the increase in exercise capacity during treatment with bosentan.

In this study, we showed that the beneficial treatment effect of bosentan, i.e. the improvement of 6-MWD, was significantly related to RV contraction duration at baseline. In PH, prolonged RV contraction duration and leftward ventricular septal bowing are associated with LV impaired diastolic filling and reduced stroke volume according to the Frank-Starling mechanism.4, 11, 30 In the present study, a RV contraction duration >550 ms was predictive for an increase in 6-MWD after bosentan treatment (sensitivity 83%, specificity 83%).

Elevated endothelin-1 levels, as can be found in PH, are associated with prolongation of action potential duration and RV contraction duration. 7-9 In patients with PH, Marcus et al. found an association between prolongation of the RV contraction duration and interventricular dyssynchrony.4 Similarly, we found that RV contraction duration at baseline was prolonged in all patients. Conversely, endothelin-1 blockade results in normalization of action potential duration.7, 8 Additionally, bosentan treatment improves LV early diastolic filling and stroke volume in patients with PH, as reported by Galiè et al.11 Accordingly, we found that improvement in 6-MWD correlated with a reduction of RV contraction duration and

Figure 3. From elevated endotheline-1 levels to reduced stroke volume. Flowchart of the proposed mechanism by which elevated endothelin-1 levels results in leftward ventricular septal bowing, which relates to a decreased left ventricular early diastolic filling and a reduced stroke volume in patients with pulmonary hypertension.

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leftward ventricular septal bowing (measured by eccentricity index). Consequently, we found a significant improvement of LV early diastolic relaxation and an increase of LV end-diastolic area index after 1 year bosentan treatment.

Our findings support the hypothesis that a positive effect of treatment with bosentan is not only due to a decrease in pulmonary vascular resistance10 but also results from a decrease in RV contraction duration (figure 3), due in part to a reduction in RV action potential duration.31 Probably, both mechanisms contribute to the beneficial effect of bosentan and may occur concomitantly. Although treatment effect of bosentan is promising, the usefulness of echocardiography in assessing long-term response to treatment as well as acute changes in the clinical status of patients with PH is unknown.

Study limitations

Firstly, patient numbers are limited. Due to the small sample size, analysis in subpopulations could not be performed. Secondly, invasive measurements of haemodynamic parameters were not performed. However, echocardiography was shown to be a reliable method to non-invasively assess systolic pulmonary arterial pressure, and RV and LV systolic and diastolic function in patients with PH. Additional studies in larger patient populations are needed to establish whether analysis of RV contraction duration may be used to identify patients who will benefit from bosentan treatment.

ConclusionOne year bosentan treatment resulted in an improved exercise capacity in 67% of the patients with pulmonary arterial hypertension associated with congenital heart disease and chronic thromboembolic PH patients. The improvement in 6-MWD was associated with a reduction of RV contraction duration and leftward ventricular septal bowing. A RV contraction duration >550 ms measured at baseline may be used to identify patients who may benefit from bosentan treatment.

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Reference List 1 Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res

2004;61:227-37.

2 Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-9.

3 Huez S, Vachiery JL, Unger P, Brimioulle S, Naeije R. Tissue Doppler imaging evaluation of cardiac adaptation to severe pulmonary hypertension. Am J Cardiol 2007;100:1473-8.

4 Marcus JT, Gan CT, Zwanenburg JJ, Boonstra A, Allaart CP, Gotte MJ, Vonk-Noordegraaf A. Interven-tricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak shortening is related to right ventricular overload and left ventricular underfilling. J Am Coll Cardiol 2008;51:750-7.

5 Marcus JT, Vonk-Noordegraaf A, Roeleveld RJ, Postmus PE, Heethaar RM, Van Rossum AC, Boon-stra A. Impaired left ventricular filling due to right ventricular pressure overload in primary pulmonary hypertension: noninvasive monitoring using MRI. Chest 2001;119:1761-5.

6 Gan CT, Lankhaar JW, Marcus JT, Westerhof N, Marques KM, Bronzwaer JG, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 2006;290:H1528-H1533.

7 Yorikane R, Koike H, Miyake S. Electrophysiological effects of endothelin-1 on canine myocardial cells. J Cardiovasc Pharmacol 1991;17 Suppl 7:S159-S162.

8 Mohacsi A, Magyar J, Tamas B, Nanasi PP. Effects of endothelins on cardiac and vascular cells: new ther-apeutic target for the future? Curr Vasc Pharmacol 2004;2:53-63.

9 Wolkart G, Stromer H, Brunner F. Calcium handling and role of endothelin-1 in monocrotaline right ventricular hypertrophy of the rat. J Mol Cell Cardiol 2000;32:1995-2005.

10 Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Raini-sio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-23.

11 Galie N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T, Espinola-Zavaleta N, Rocchi G, Manes A, Frantz R, Kurzyna M, Nagueh SF, Barst R, Channick R, Dujardin K, Kronenberg A, Leconte I, Rainisio M, Rubin L. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:1380-6.

12 Bonderman D, Nowotny R, Skoro-Sajer N, Jakowitsch J, Adlbrecht C, Klepetko W, Lang IM. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2599-603.



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ent response



16 Hoeper MM, Kramm T, Wilkens H, Schulze C, Schafers HJ, Welte T, Mayer E. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2363-7.

17 Gatzoulis MA, Beghetti M, Galie N, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: Results of the BREATHE-5 open-label extension study. Int J Cardiol 2007;127:27-32.

18 Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.


20 Duffels MG, Vis JC, van Loon RL et al. Down patients with Eisenmenger syndrome: Is bosentan treat-ment an option? Int J Cardiol. In press 2008.

21 Chua RF, Keogh AM FAU, Byth KF, O’Loughlin A. Comparison and validation of three measures of qual-ity of life in patients with pulmonary hypertension. Int Med J 2006;36:705-10.



24 Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up of patients with pulmonary thromboem-bolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151-8.


26 Schiller NB, Shah PM, Crawford M, Demaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, . Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-67.

27 Ryan T, Petrovic O, Dillon JC, Feigenbaum H, Conley MJ, Armstrong WF. An echocardiographic index for separation of right ventricular volume and pressure overload. J Am Coll Cardiol 1985;5:918-27.

28 Tei C New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol 1995;26:135-6.

29 Rondelet B, Kerbaul F, Motte S, Van BR, Remmelink M, Brimioulle S, McEntee K, Wauthy P, Salmon I, Ketelslegers JM, Naeije R. Bosentan for the prevention of overcirculation-induced experimental pulmo-nary arterial hypertension. Circulation 2003;107:1329-35.

30 Roeleveld RJ, Marcus JT, Faes TJ, Gan TJ, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Interventricu-lar septal configuration at mr imaging and pulmonary arterial pressure in pulmonary hypertension. Radi-ology 2005;234:710-7.

31 Matsumoto Y, Aihara H, Yamauchi-Kohno R, Reien Y, Ogura T, Yabana H, Masuda Y, Sato T, Komuro I, Nakaya H. Long-term endothelin a receptor blockade inhibits electrical remodeling in cardiomyopathic hamsters. Circulation 2002;106:613-9.

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1111Chapter 11

Atherosclerosis in patients with cyanotic congenital heart disease

Mariëlle GJ Duffels, Karlijn M Mulder, Mieke D Trip, Erik de Groot, Johan Gort,

Arie PJ van Dijk, Elke S Hoendermis, Luciano Daliento, Aeiko H Zwinderman, Rolf MF Berger,

Barbara JM Mulder.

Submitted


AbstractBackground: Cyanotic patients with congenital heart disease might be protected against atherosclerosis. To understand this causality, we investigated carotid intima-media thickness (IMT) and risk factors for atherosclerosis in cyanotic patients with congenital heart disease and controls.

Methods: We investigated the atherosclerotic risk profiles and carotid IMT in 54 adults with cyanotic congenital heart disease and in 54 unaffected age- and sex-matched controls.

Results: Fifty-four cyanotic patients (30 males, mean age 38, range 19-60 years) and 54 age- and sex-matched controls were included. Mean transcutaneous saturation of the cyanotic patients was 81 ± 6%. Mean carotid IMT, adjusted for age was significantly decreased in cyanotic patients compared to controls (0.55 ± 0.1 mm vs. 0.58 ± 0.08 mm: ΔIMT =0.04(SE 0.015) mm, p=0.01). Moreover, atherosclerotic disease risk was reduced. In cyanotic patients we observed lower total cholesterol levels (4.4 ± 1 mmol/L vs 4.9 ± 1 mmol/L; p=0.02), lower thrombocyte levels (173 ± 81 10E9/L vs. 255 ± 54 10E9/L; p<0.01), higher bilirubin levels (18.6 ± 11 umol/L vs. 12.7 ± 6 umol/L; p<0.01), and lower diastolic and systolic blood pressure (respectively 71 ± 9 mmHg vs. 76 ± 9 mmHg; p<0.01 and 113 ± 14 mmHg vs. 124 ± 12 mmHg; p<0.01).

Conclusion: In patients with cyanotic congenital heart disease carotid IMT, and hence atherosclerosis disease risk, was decreased. This reduction in cyanotic patients might be due to a combination of reduced atherogenic risk factors like lower blood pressure, lower total cholesterol levels, higher bilirubin levels and lower thrombocyte levels.

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IntroductionLiterature indicates patients in cyanotic state with congenital heart disease (CHD) might protect against atherosclerosis.1, 2 Cyanosis is the result of persistent venous to arterial mixing due to a pulmonary-to-systemic shunt. In around 1% of CHD patients, cyanosis results from the development of the Eisenmenger syndrome.3 This syndrome is characterized by severe irreversible pulmonary vascular disease and reversal of the previous systemic-to-pulmonary shunt.4-7

Cyanosis in CHD patients is associated with haemostatic abnormalities involving platelets and coagulation mechanisms resulting in an increased risk for bleeding and thrombosis.8, 9 In a study of Perloff et al., signs of atherosclerosis at coronary angiography and in necropsy specimens were missing in cyanotic patients.1 Moreover, cyanosis was associated with increased antithrombotic and antiatherogenic effects such as thrombocytopenia and hyperbilirubinemia.10 In addition, high altitude hypoxemia was related with a reduced total cholesterol and LDL cholesterol in combination with elevated HDL cholesterol.1, 2

Atherosclerosis is a dynamic process characterized by vessel wall remodelling, ultimately leading to an acute cardiovascular event.11 Non-invasive B-Mode ultrasound imaging of carotid intima media thickness (IMT) allows for the assessment of early atherosclerotic changes. Carotid IMT is an accepted valid marker for present status of atherosclerosis and future atherosclerotic disease risk.11-13 Carotid IMT of cyanotic CHD patients has not yet been studied. In this study, we hypothesize that IMT, and hence the atherosclerotic burden, is decreased in cyanotic patients compared to controls. We hypothesize that a decreased IMT is accompanied by reduced atherogenic risk factors. We therefore compared IMT and risk factors for atherosclerosis between adult patients with cyanotic CHD and unaffected age- and sex-matched controls.

Methods

Patient population

For the present study, patients were included from 7 hospitals (e.g. Academic Medical Center Amsterdam, University Medical Center Groningen, Radboud University Nijmegen Medical Center, Leiden University Medical Center, University Medical Center Utrecht, St. Antonius Hospital Nieuwegein, and University of Padua (Italy)). Patients with a transcutaneous oxygen saturation below 90% at rest were defined cyanotic. Cyanotic CHD patients from the Netherlands were identified using the CONCOR database (a national registry- and DNA-bank of adult patients with congenital heart disease in the Netherlands).14 Italian cyanotic patients were identified at the outpatient clinic. Patients were requested to participate by their cardiologist. Patients with one of the following defects were asked to participate: ‘Eisenmenger syndrome’, ‘univentriculair heart’, ‘pulmonary artesia with ventricular septal defect (VSD)’, ‘pulmonary atresia without VSD’, or ‘double outlet right ventricle’. Age- and

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therosclerosis in cyanotic patients


sex-matched controls were recruited among relatives and acquaintances by the participating patients. Patients with a liver or kidney disease, myeloproliferative disease, current or recent malignancy and patients using lipid-lowering drugs were excluded from this study.

Study protocol

This was an observational, case-control study. Data were collected during a single visit to the outpatient clinic between March 2007 and May 2008. Data on coronary risk profile (body mass index, diastolic and systolic blood pressure, current smoking status, positive family history (parent or sibling with a cardiovascular event < 55 years)), medical history and use of medication (thiazide diuretics, beta-blockers, and lipid lowering drugs) were collected both in cyanotic patients and in controls. Hypertension was defined as a diastolic blood pressure > 90 mmHg, a systolic blood pressure > 140 mmHg, or the use of antihypertensive agents. Furthermore, a fasting venous blood sample was collected. Haematologic measurements included haemoglobin concentration, haematocrit, thrombocyte, and erythrocyte count. Haematocrit was based on automated electronic particle counts. Serum tests included glucose, uric acid, total bilirubin, folate acid and measurement of lipids. Transcutaneous saturation was measured in both patients and controls after 5 minutes of rest using a standard transcutaneous pulse oximeter at the finger.

Atherosclerotic changes were assessed in both cyanotic patients and controls by measuring the carotid IMT using B-mode ultrasound. IMT-images of the arterial far wall segments of the right and left common carotid artery, carotid bulb and, internal carotid artery were acquired according to a standardized protocol.11 Carotid ultrasound scans of the patients from the Academic Medical Center Amsterdam, Leiden University Medical Center, University Medical Center Utrecht, Radboud University Nijmegen Medical Center and the St. Antonius Hospital Nieuwegein, The Netherlands, were performed in the Academic Medical Center Amsterdam by a single well trained and experienced sonographer. IMT measurements of subjects of the University Medical Center Groningen (n=13) and the University of Padua (n=6) were performed in the respective centers. In all centers, including the Italian site, scan protocols were standardized. The centers in the Netherlands used Acuson Aspen or Sequoia equipment (using L7 transducers and the magnification settings on both machine types) (Siemens, Erlangen, Germany). In the Padua center images were measured on-line using a Acuson Sequoia (C512, echocardiography system, 4V1C transthoracic Sector Array Transducer and 6L3 IMT Sector Array Transducer) (Siemens). Dynamic and high resolution still images were saved as DICOM files. Measurements were done on the 2 x 2 cm still frames; the clips were used as a dynamic reference to identify the lumen-intima and media-adventitia interfaces of the arterial far walls. All images were analyzed by the same image analyst blinded to clinical information. IMT was defined as the average value of the IMT’s of the right and left common carotid artery, carotid bulb and internal carotid artery segments. The institutional review committee approved the protocol and a written informed consent was obtained from

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all participants prior to participation in the study. For patients with Down syndrome, parental consent was obtained.


The descriptive data are presented as mean with standard deviation if normally distributed or as median with range as appropriate. Comparisons of continuous variables between groups were made by unpaired Student t-tests. In case of a skewed distribution, the Mann-Whitney U test was used. Correlation coefficients were used to assess the relation between IMT and age and total cholesterol. Multivariate analysis of mean IMT, total cholesterol levels and HDL cholesterol levels was used to assess contributing parameters. A value of p < 0.05 was considered to be significant.

Results

Patient population

Between March 2007 and May 2008, 54 cyanotic patients (30 males and 24 females, mean age 38, range 19-60 years) and 54 age- and sex-matched controls were included in this study. Mean transcutaneous saturation of the cyanotic patients was 81 ± 6%. Eisenmenger syndrome was present in 89% of the cyanotic patients (n=48), with VSD being the most frequent underlying diagnosis. Of the cyanotic patients 35% (n=19) had Down syndrome of whom 68% (n=13) had hypothyroidism. All patients with hypothyroidism were adequately treated.

Table 1. Characteristics of the study population

Cyanotic CHD(n=54)

Controls(n=54)

p-value

Age, mean, range (years) 38 (19-60) 37 (18-60) 0.3

Gender, male, n (%) 30 (56) 29 (54) 0.5

Mean oxygen saturation, mean ± SD (%) 81±6 100±0.7 <0.01

Blood pressure, mean ± SD

Diastolic (mm Hg) 71±9 76±9 <0.01

Systolic (mm Hg) 113±14 124±12 <0.01

Risk factors atherosclerosis

Thrombotic events, n (%) 6 (11) 2 (4) 0.1

Hypertension, n (%) 3 (6) 9 (17) 0.06

BMI > 30 kg/m², n (%) 4 (7) 5 (9) 0.5

Hypothyroidism, n (%) 13 (24) 0 <0.01

Positive family history CVD, n (%) 5 (9) 5 (9) 0.6

Smoking, n (%) 3 (6) 8 (15) 0.1

CHD = congenital heart disease, BMI = body mass index, CVD = cardiovascular disease

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Cyanotic patients had significantly lower diastolic and systolic blood pressure compared to controls (respectively 71 ± 9 mmHg vs. 76 ± 9 mmHg; p=0.02 and 113 ± 14 mmHg vs. 124 ± 12 mmHg; p<0.01). Table 1 shows the population characteristics. One cyanotic patient had a previous cerebrovascular accident and 6 cyanotic patients had a previous thrombotic event.

Intima-media thickness

The results of the B-mode ultrasound IMT measurements showed IMT increase with advancing age (r = 0.4, p<0.01). Moreover, mean carotid IMT, adjusted for age using linear regression analysis, was significantly decreased in cyanotic patients compared to controls (0.55 ± 0.1 mm vs. 0.58 ± 0.08 mm) with a mean difference of 0.04 mm (SE 0.015 mm, p = 0.01), as shown in figure 1. Sub-segmental analysis, after adjustment for age, showed these differences to be most explicit in the common carotid artery (p = 0.02) and carotid bulb (p = 0.004). There was no age*gender interaction in IMT (p = 0.9). In multivariate analysis, the presence of Down syndrome, hypothyroidism, current smoking or the use of thiazide diuretics or beta-blockers and uric acid levels had no contributing effect on differences between cyanotic patients and controls. In addition, after adjustment for diastolic and systolic blood pressure, mean IMT was comparable in both groups with a mean difference of 0.026 mm (SE 0.017 mm, p= 0.1). Moreover, a positive association was found between IMT and diastolic and systolic blood pressure (respectively r = 0.3, p < 0.01 and r = 0.3, p < 0.01). No correlations were observed between the decreased blood pressure and the use of B-blockers or diuretics.

Figure 1. In this figure mean carotid IMT, adjusted for age, is shown. Carotid IMT was significantly decreased in cyanotic patients compared to controls with a mean difference of 0.04 mm (SE 0.015 mm, p=0.01).

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Blood analyses

To clarify the cause of the difference in IMT between cyanotic patients and controls, we analyzed risk factors for atherosclerosis through blood analysis (table 2). Total cholesterol levels were significantly lower in cyanotic patients compared to controls (figure 2) and reduced total cholesterol levels (< 3.9 mmol/L) were more often seen in these patients (37% vs 17%, p=0.02). Total cholesterol was positively associated with mean IMT (r = 0.4, p<0.01) and with oxygen saturation (r = 0.2, p=0.04). In multivariate analysis, the presence of Down syndrome, hypothyroidism, smoking or the use of thiazide diuretics or beta-blockers had no contributing effect on differences in total cholesterol between cyanotic patients and controls. Table 2 shows the equal distribution of LDL-cholesterol in both groups. Strikingly, HDL-cholesterol was significantly lower in cyanotic patients. Multivariate analysis indicated that 32% of the variation in HDL was due to the cyanotic state and the use of beta-blockers (r = 0.6, p < 0.001). In addition, there were no gender differences in total, LDL- and HDL-cholesterol.

Additional blood analyses showed, as expected, significantly increased haemoglobin, haematocrit and erythrocyte levels in cyanotic patients, as well as bilirubin- and uric acid levels (table 2). No correlation was found between either haemoglobin, haematocrit or erythrocyte levels and total cholesterol. Total cholesterol was neither related with bilirubin nor with uric acid levels. Furthermore, 46% of the cyanotic patients (n=25) had thrombocytopenia (e.g. platelet counts <150x109/L). Thrombocyte levels were associated with the severity of cyanosis (r= 0.5, p<0.01).

Figure 2. Total fasting cholesterol of cyanotic patients and controls. Total cholesterol was significantly reduced in cyanotic patients compared to controls with respectively 4.4 ± 1 mmol/L versus 4.9 ± 1 mmol/L (p=0.02).

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DiscussionThis is the first study showing a reduced IMT in cyanotic CHD patients by means of non-invasive techniques. The reduction in IMT might be due to a combination of decreased atherogenic risk factors in cyanotic patients.

Our results are in accordance with the findings of Perloff et al., who found minimal or absent signs of atherosclerosis on coronary angiographies in 25 cyanotic females (mean age 43 ± 4 years) and 24 cyanotic males (mean age 41 ± 6 years).1 We confirmed these findings using non-invasive and quantitative carotid IMT measurements.

It is known that reduced atherogenic and thrombotic factors, e.g. hypocholesterolemia, hyperbilirubinemia, elevated nitric oxide levels and thrombocytopenia are associated with cyanosis.1, 2, 15 To further elucidate the mechanism underlying the cause of the reduced mean IMT in cyanotic patients, we analyzed these risk factors. Elaborating the contribution of nitric oxide to IMT was beyond the scope of our study.

Total cholesterol levels were significantly reduced in our patients, and correlated positively with decreased oxygen saturation. Decreased total cholesterol related with low IMT, as has been demonstrated in the general population.16-18

Hyperbilirubinemia is frequently seen in cyanotic patients due to secondary erythrocytosis, as confirmed in our study.19 Serum bilirubin is considered antiatherogenic as it is an endogenous antioxidant that inhibits LDL oxidation.20 However, we were unable to demonstrate a reduction in serum LDL levels, as the inhibitive properties of hyperbilirubinemia were

Table 2. Bloodanalyses of cyanotic patients and controls

Cyanotic CHD(n=54)

Controls(n=54)

p-value

Serum lipids (mmol/L)

Total cholesterol 4.4 ± 1.2 4.9 ± 1.0 0.02

LDL-cholesterol 2.8 ± 1 2.9 ± 0.9 0.5

HDL-cholesterol 1.2 ± 0.3 1.6 ± 0.4 <0.01

Triglycerides 1 ± 0.5 0.9 ± 0.4 0.1

Serum tests

Bilirubin total (umol/L) 18.6 ± 11 12.7 ± 6 <0.01

Uric acid (mmol/L) 0.5 ± 0.7 0.3 ± 0.08 0.03

Glucose (mmol/L) 4.6 ± 0.9 4.8 ± 0.5 0.2

Folate acid (nmol/L) 21.5 ± 13 24.8 ± 6 0.2

Haematology

Haemoglobin (mmol/L) 11.9 ± 2 8.9 ± 0.8 <0.01

Haematocrit (L/L) 0.59 ± 0.09 0.42 ± 0.04 <0.01

Erythrocytes (10E12/L) 6.7 ± 1.2 4.7 ± 0.5 <0.01

Thrombocytes (10E9/L) 173 ± 81 255 ± 54 <0.01

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counteracted by elevated uric acid levels, which promotes LDL oxidation.21 Unexpectedly, we found decreased HDL levels in the cyanotic population. The cyanotic state and the use of beta-blockers were found independent predictors. Beta-blocker usage has previously been shown to negatively influence HDL cholesterol levels.22, 23

Blood pressure was significantly reduced in our patients and an association was found between diastolic and systolic blood pressure and IMT. In multivariate analysis the reduced blood pressure could not explain the difference in IMT between patients and healthy controls.

Although not a risk factor for atherosclerosis, thrombocytopenia is frequently seen in cyanotic patients.8, 10, 24, 25 We found thrombocyte levels to be negatively associated with the severity of pulmonary-to-systemic shunting and therefore with the level of cyanosis. Contrary to the increased bleeding tendency caused by this thrombocytopenia, hyperviscosity, which is a frequent complication in cyanotic patients, increases thrombotic risk. We confirmed this increased hyperviscosity, by demonstrating significantly elevated haemoglobin, haematocrit and erythrocyte levels in cyanotic patients. 9, 26, 27 However, the literature is ambiguous on the thrombotic risk of hyperviscosity, indicating the necessity for further investigation.27-30

A limitation of our study is the small difference in IMT between two small and relatively young populations. Actually, the IMT is within normal range31 and both groups would be estimated to be at low risk for cardiovascular event. Additionally, long-term outcome is unknown in our population and regularly follow-up has to prove whether a reduced IMT in cyanotic patients is associated with a decreased risk for cardiovascular events. Moreover, the underlying congenital heart defects leading to cyanosis were heterogenic which made the size of subgroups limited. Another limitation is the lack of angiographic information of the coronary tree at time of the carotid ultrasound scans.

ConclusionOur study showed lower carotid IMT values in cyanotic CHD patients compared to unaffected controls, as measured by non-invasive ultrasound. The comparative decrease in carotid IMT might be due to a combination of reduced atherogenic risk factors, including lower blood pressure, lower total cholesterol levels, and higher bilirubin levels in cyanotic patients. The reduction in IMT in cyanotic patients might be due to a combination of reduced atherogenic risk factors like lower blood pressure, lower total cholesterol levels, higher bilirubin levels and lower thrombocyte levels. Therefore, in contrast to acyanotic CHD patients, it might be not likely that atherosclerosis will pose an additional health problem to cyanotic CHD patients when they grow older and reach the age at which atherosclerosis becomes clinically relevant.

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8 Perloff JK Systemic complications of cyanosis in adults with congenital heart disease. Hematologic derangements, renal function, and urate metabolism. Cardiol Clin 1993;11:689-99.

9 Oechslin E Hematological management of the cyanotic adult with congenital heart disease. Int J Cardiol 2004;97 Suppl 1:109-15.

10 Lill MC, Perloff JK, Child JS. Pathogenesis of thrombocytopenia in cyanotic congenital heart disease. Am J Cardiol 2006;98:254-8.

11 Groot de E, Hovingh GK, Wiegman A, Duriez P, Smit AJ, Fruchart JC, Kastelein JJ. Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation 2004;109:III33-III38.

12 Bots ML, Baldassarre D, Simon A, de GE, O’Leary DH, Riley W, Kastelein JJ, Grobbee DE. Carotid inti-ma-media thickness and coronary atherosclerosis: weak or strong relations? Eur Heart J 2007;28:398-406.

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16 Howard G, Sharrett AR, Heiss G, Evans GW, Chambless LE, Riley WA, Burke GL. Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC Investigators. Stroke 1993;24:1297-304.

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17 Juonala M, Kahonen M, Laitinen T, Hutri-Kahonen N, Jokinen E, Taittonen L, Pietikainen M, Helen-ius H, Viikari JS, Raitakari OT. Effect of age and sex on carotid intima-media thickness, elasticity and brachial endothelial function in healthy adults: The Cardiovascular Risk in Young Finns Study. Eur Heart J 2008;29:1198-206.

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19 Rosove MH, Perloff JK, Hocking WG, Child JS, Canobbio MM, Skorton DJ. Chronic hypoxaemia and decompensated erythrocytosis in cyanotic congenital heart disease. Lancet 1986;2:313-5.

20 Madhavan M, Wattigney WA, Srinivasan SR, Berenson GS. Serum bilirubin distribution and its relation to cardiovascular risk in children and young adults. Atherosclerosis 1997;131:107-13.

21 Rich MW Uric acid: is it a risk factor for cardiovascular disease? Am J Cardiol 2000;85:1018-21.

22 Wallace RB, Hunninghake DB, Reiland S, Barrett-Connor E, Mackenthun A, Hoover J, Wahl P. Alter-ations of plasma high-density lipoprotein cholesterol levels associated with consumption of selected medications. The Lipid Research Clinics Program Prevalence Study. Circulation 1980;62:IV77-IV82.

23 Madu EC, Reddy RC, Madu AN, Anyaogu C, Harris T, Fraker TD, Jr. Review: the effects of antihyper-tensive agents on serum lipids. Am J Med Sci 1996;312:76-84.

24 Levine RF, Eldor A, Shoff PK, Kirwin S, Tenza D, Cramer EM. Circulating megakaryocytes: delivery of large numbers of intact, mature megakaryocytes to the lungs. Eur J Haematol 1993;51:233-46.

25 Geddis AE, Kaushansky K. Immunology. The root of platelet production. Science 2007;317:1689-91.

26 DeFilippis AP, Law K, Curtin S, Eckman JR. Blood is thicker than water: the management of hyperviscos-ity in adults with cyanotic heart disease. Cardiol Rev 2007;15:31-4.

27 Perloff JK, Rosove MH, Child JS, Wright GB. Adults with cyanotic congenital heart disease: hematologic management. Ann Intern Med 1988;109:406-13.

28 Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilen U, Kaemmerer H, Moons P, Meij-boom F, Popelova J, Laforest V, Hirsch R, Daliento L, Thaulow E, Mulder B. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005;26:2325-33.

29 Ammash N, Warnes CA. Cerebrovascular events in adult patients with cyanotic congenital heart disease. J Am Coll Cardiol 1996;28:768-72.

30 Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circula-tion 1993;87:1954-9.

31 Juonala M, Kahonen M, Laitinen T, Hutri-Kahonen N, Jokinen E, Taittonen L, Pietikainen M, Helenius H, Viikari JS, Raitakari OT. Effect of age and sex on carotid intima-media thickness, elasticity and brachi-al endothelial function in healthy adults: The Cardiovascular Risk in Young Finns Study. Eur Heart J 2008;29:1198-206.

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1212Chapter 12

Summary & Samenvatting


SummaryIn patients with congenital heart disease (CHD), pulmonary arterial hypertension (PAH) may develop due to an increased pulmonary arterial flow as a result of a left-to-right shunt. PAH may lead to decreased functional capacity and right ventricular failure, and is often associated with early death. The Eisenmenger syndrome is the final stage of PAH, characterized by such severe, and irreversible PAH that the intra-cardiac shunt reverses, leading to cyanosis. In this thesis we focused on adult patients with congenital heart disease with PAH and the Eisenmenger Syndrome.

Chapter 1 gives an overview of the development, incidence, clinical presentation, prognosis and treatment strategies of PAH associated with CHD.

In chapter 2 and 3 we described the prevalence of PAH in patients with congenital heart disease. In chapter 2 we determined the prevalence of PAH using data from the CONCOR (CONgenital COR vitia) registry, a nationwide registry of adult patients with congenital heart disease in the Netherlands. In this patient population (n=5970), PAH is frequently seen with a prevalence of at least 4.2%. We found PAH to be particularly common in patients with a septal defect (prevalence is 6%), even if the defect had been closed (prevalence is 3%). More than half of these patients had developed the Eisenmenger syndrome, which accounts for 1% of the total population in the CONCOR registry. In chapter 3, we assessed the prevalence of PAH in 1877 adults with a septal defect using data from the Euro Heart Survey, a retrospective cohort study with a 5-year follow-up period. Furthermore, Survey data were used to evaluate the relation of PAH with patient characteristics and outcomes. We found PAH to be common (in 34% and 12% of patients with an open or a closed ASD and 28% and 13% of patients with an open or a closed VSD, respectively). Patients with PAH were predisposed to develop severe functional limitations and clinical deterioration, even when the defect had previously been closed, and in patients who had not developed the Eisenmenger syndrome.

Until recently, treatment options for patients with PAH associated with CHD were limited to preventing and treating complications. In the past decade, new medical treatment strategies, such as (intravenous) prostacyclin, endothelin receptor antagonists (ERA), and phosphodiesterase-5-inhibitors (PDE-5), have been demonstrated to improve survival of patients with PAH. However, experience in adult patients with CHD is limited. In chapter 4 we described medium-term follow-up of 15 adult patients with PAH associated with CHD, who received different types of medication. These medications consisted of either intravenous prostacyclin, endothelin receptor antagonists, or phosphodiesterase-5-inhibitors. We showed that these therapeutical treatment strategies are safe and well tolerated. In addition, it appeared that the medium-term treatment effect of either mono- or combination therapy is one of disease stabilization and decreasing the rate of deterioration.

In chapter 5 we evaluated (4 months) and long-term bosentan effects (≥ 2 years) in 20 adults and 10 children with PAH associated with a systemic-to-pulmonary shunt. At 4 months of follow-up, WHO class and 6-minute walk distance had significantly improved in both adults and children. During long-term follow-up, this improvement persisted throughout

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the first year but declined thereafter (but returned to baseline values thereafter). In children, a progressive decline in exercise capacity was observed after this first year, whereas in adults, improvement lasted longer. We suggested that the difference in treatment effect may have been confounded by differences in cardiac pathology and disease severity.

Patients with Down syndrome are frequently diagnosed with CHD. Until the 1970s these defects often remained uncorrected, leading to a high prevalence of PAH in this patient population. Moreover, patients with Down syndrome develop PAH earlier and it has more violent course. Nonetheless, the therapeutic role of bosentan in patients with Down syndrome and the Eisenmenger syndrome remains unknown, as these patients had not been included in most studies. In chapter 6 we evaluated the safety and tolerability of oral bosentan therapy in Down patients with Eisenmenger syndrome. Treatment with bosentan proved to be safe and well tolerated. Moreover, our results suggested an improvement of exercise tolerance during the first 3 months of bosentan treatment, after which 6-minute walk distance slowly returned to baseline value. Treatment effects did not differ from those observed in Eisenmenger patients without Down syndrome. Based on our data, we concluded that patients with Down syndrome could also benefit from bosentan treatment when they have Eisenmenger syndrome.

In chapter 7, we described the short- and longer-term treatment effect of bosentan in both patients with and without Down syndrome. In this study, 58 patients (>18 years) with PAH associated with CHD were treated with bosentan. All patients were evaluated at baseline and during follow-up with laboratory tests, 6-minute walk test, quality of life questionnaires, and Doppler echocardiography. We analyzed treatment efficacy separately within patients with (n=28) and without (n=30) Down syndrome. In the patients with Down syndrome, 6-MWD and quality of life remained stable during treatment. However, in patients without Down syndrome, mean 6-minute walk distance (6-MWD) increased from 427 ± 97 m to 461 ± 104 m (p<0.01) after 6 months of treatment, followed by a gradual return to baseline and disease stabilization. Quality of life improved significantly during treatment, and remained high during an 18 months follow-up period (p<0.05). In conclusion, the effect of bosentan treatment could not be established in patients with Down Syndrome, due to the unavailability of validated outcome parameters. However, we found that longer-term treatment with bosentan induced stabilization of exercise capacity and a persistent improvement of quality of life in patients without Down syndrome.

In chapter 8 we studied the influence of duration of pulmonary vessel changes on one year of bosentan treatment in 18 adult patients with life-long pulmonary vessel changes (PAH due to CHD) and in 16 adult patients with subacutely induced pulmonary vessel changes (CTEPH). All patients were evaluated at baseline and during follow-up by means of the 6-minute walk test and laboratory tests. Surprisingly, improvement of the 6-minute walk distance was comparable in both patient groups during treatment with bosentan. Mean 6-minute walk distance improved significantly during the first three months of treatment, and stabilized the following 9 months thereafter. Although duration of pulmonary vessel changes is

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strikingly different, treatment effect of bosentan was comparable. The main treatment effect seems to be one of disease stabilization and decreasing the rate of deterioration.

A commonly used primary endpoint to study the effectiveness of medical therapy in patients with PAH is the 6-minute walk distance. In patients with severe PAH (WHO/NYHA III and IV) changes in 6-minute walk distance correlated to changes in hemodynamic severity of disease. However, in mildly impaired patients (WHO/NYHA II), significant improvements in hemodynamics were accompanied by non significant or absent improvement in 6-minute walk distance. Therefore, in chapter 9, we discussed whether the 6-minute walk distance is an appropriate outcome parameter in patients with mild PAH. We studied aerobic capacity during maximal cardio pulmonary exercise testing and six-minute walk test in 8 mildly and 13 severely impaired patients with PAH due to CHD or patients with chronic thromboembolic pulmonary hypertension, and 8 healthy controls. We showed that in mildly impaired patients, the 6-minute walk test does not reflect maximal aerobic capacity whereas in severely impaired PAH patients, the 6-minute walk test indeed reflects maximal aerobic capacity. Therefore, we concluded that the 6-minute walk test may not be an appropriate diagnostic tool of treatment response in mildly impaired PAH patients.

In chapter 10 we described the potential usefulness of echocardiographically measured right ventricular (RV) contraction duration as predictor of treatment response in 9 patients with PAH associated with congenital heart disease (CHD) and in 9 patients with chronic thromboembolic pulmonary hypertension (CTEPH). RV contraction duration was measured from the onset of the QRS complex to the onset of early diastolic filling of the RV (E). A prolonged RV contraction duration results in leftward ventricular septal bowing and impaired left ventricular (LV) early diastolic filling. As it has been previously shown that not all patients with PH show improvement of exercise capacity during treatment we investigated whether RV contraction duration at baseline is a predictor of improvement in exercise capacity and if RV contraction duration shortening during treatment is associated with an increase in exercise capacity. In 67% of the patients, one year bosentan treatment resulted in an improved exercise capacity. This improvement was associated with a reduction of RV contraction duration and leftward ventricular septal bowing. Moreover, a baseline RV contraction duration >550 ms was associated with improved 6-minute walk distance (sensitivity 83%, specificity 83%; p<0.01). Based upon our data, we suggest that RV contraction duration measured at baseline may be used to identify patients who may benefit from bosentan treatment.

In chapter 11, we investigated the carotid intima media thickness (IMT) and risk factors for atherosclerosis in 54 cyanotic CHD patients and 54 age- sex matched controls. Mean carotid IMT, adjusted for age was significantly decreased in cyanotic CHD patients compared to controls (0.55 ± 0.1 mm vs. 0.58 ± 0.08 mm) with a mean difference of 0.04 mm (SE 0.015 mm, p=0.01). This reduction might be due to a combination of decreased atherogenic risk factors. In cyanotic patients total cholesterol levels were reduced together with elevated bilirubimia and decreased blood pressure. Therefore, we suggest that in contrast to acyanotic CHD patients, it might be unlikely that atherosclerosis will pose an additional health problem

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to cyanotic CHD patients when they grow older and reach the age at which atherosclerosis becomes clinically relevant.

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SamenvattingPatiënten met een aangeboren hartafwijking kunnen pulmonale arteriële hypertensie (PAH) ontwikkelen als gevolg van een toegenomen bloedstroom over de arteria pulmonalis ten gevolge van een links-rechts shunt. PAH kan leiden tot een verminderde inspanningscapactiteit, rechter ventrikel falen en vroegtijdig overlijden. Het Eisenmenger syndroom is de meest extreme en irreversibele vorm van PAH, waarbij de hoge druk in de pulmonaal arteriën leidt tot een omkering van de initiële links-rechts shunt en het ontstaan van cyanose. In dit proefschrift ligt de focus op volwassen patiënten met een aangeboren hartafwijking met PAH en op patiënten met het Eisenmenger syndroom.

Hoofdstuk 1 geeft een overzicht van het ontstaan, de incidentie, klinische presentatie, prognose en behandelingsmogelijkheden van PAH geassocieerd met aangeboren hartaf-wijkingen.

In hoofdstuk 2 en 3 beschrijven wij de prevalentie van PAH bij patiënten met een aangeboren hartafwijking. In hoofdstuk 2 bepaalden wij de prevalentie door gebruik te maken van data van de CONCOR database, de landelijke registratiebank van volwassenen met een aangeboren hartafwijking in Nederland. In deze patiënten populatie (ten tijde van analyse n=5970) bleek PAH een frequent voorkomende aandoening met een prevalentie van tenminste 4.2%. PAH komt met name voor bij patiënten met een septum defect (prevalentie 6%), zelfs wanneer het defect chirurgisch gesloten is (prevalentie 3%). Uiteindelijk ontwikkelt meer dan de helft van de patiënten met PAH ten gevolge van een aangeboren hartafwijking het Eisenmenger syndroom, wat neerkomt op 1% van de totale CONCOR populatie. In hoofdstuk 3, evalueerden wij de prevalentie van PAH in 1877 volwassenen met een septum defect. Hierbij maakten wij gebruik van data van de Euro Heart Survey, een retrospectieve studie met een follow-up van vijf jaar. Daarnaast werd de relatie tussen patiënten karakteristieken en het optreden van PAH geanalyseerd. PAH komt veel voor respectievelijk 34% en 12% van de patiënten met een open of gesloten ASD had PAH en 28% en 13% van de patiënten met een open of gesloten VSD ontwikkelde PAH. De inspanningscapaciteit bij patiënten met PAH was ernstige verslechterd.

Tot voor kort bestond er geen behandeling voor patiënten met PAH ten gevolge van een aangeboren hartafwijking en was behandeling gericht op het voorkómen en behandelen van complicaties. Sinds een aantal jaar hebben nieuwe medicamenteuze behandelingen, met onder ander endotheline receptor antagonisten, geleid tot een betere overleving van patiënten met PAH. Echter, over het effect van endotheline receptor antagonisten bij volwassen patiënten met een aangeboren hartafwijking is weinig bekend. In hoofdstuk 4 beschrijven wij de middellange follow-up van 15 volwassen patiënten met PAH ten gevolge van een aangeboren hartafwijking die behandeld werden met verschillende vormen van medicatie. De medicatie bestond uit intraveneus prostacycline, een endotheline receptor antagonist of een fosfosdiësterase-5-remmer. Wij toonden aan dat medicamenteuze behandeling veilig is en goed verdragen wordt door patiënten met een aangeboren hartafwijking. Er zijn aanwijzingen dat middellange behandeling met zowel mono- als combinatie therapie leidt tot stabilisatie


van de ziekte en dat medicamenteuze behandeling de snelheid van klinische verslechtering vertraagd.

In hoofdstuk 5 evalueerden wij het korte (4 maanden) en lange termijn (≥2 jaar) effect van bosentan in 20 volwassenen en 10 kinderen met PAH ten gevolge van een links-rechts shunt. Na 4 maanden follow-up was de WHO klasse en de 6-minuten loop afstand significant verbeterd ten opzicht van aanvang van zowel de volwassenen als de kinderen. Deze verbetering persisteerde gedurende het eerste jaar van behandeling waarna een afname tot uitgangswaarde werd gezien. Bij de kinderen werd een progressieve afname van de inspanningscapaciteit waargenomen na dit eerste jaar, terwijl de verbetering van de inspanningscapaciteit bij volwassenen langer aanhield. Het verschil in behandel effect kan mogelijk verklaard worden door het verschil in pathologie van het hart en de ernst van de ziekte tussen volwassenen en kinderen met PAH ten gevolge van een aangeboren hartafwijking.

Bij patiënten met het syndroom van Down komen aangeboren hartafwijkingen frequent voor. Tot de jaren zeventig werden deze patiënten niet geopereerd, hierdoor bestaat er een hoge prevalentie van PAH bij patiënten met het syndroom van Down. Daarnaast ontstaat PAH bij deze patiënten eerder en is het beloop ernstiger. Echter, deze patiënten groep wordt veelal geëxcludeerd van deelname aan studies naar het effect van behandeling waardoor de therapeutische rol van bosentan bij patiënten met het syndroom van Down en het Eisenmenger syndroom onbekend is. In hoofdstuk 6 evalueerden wij de veiligheid en tolerabiliteit van behandeling met bosentan bij patiënten met het syndroom van Down en het Eisenmenger syndroom. Behandeling met bosentan van patiënten met het syndroom van Down was veilig en werd goed verdragen. Daarnaast laten onze resultaten een verbetering van inspanningscapaciteit zien gedurende de eerste drie maanden van behandeling met bosentan waarna de 6-minuten loop afstand geleidelijk afnam naar uitgangswaarde. Kortom, het behandel effect lijkt niet anders dan bij patiënten met het Eisenmenger syndroom zonder het syndroom van Down. Gebaseerd op deze data concluderen wij dat patiënten met het syndroom van Down baat kunnen hebben bij behandeling met bosentan wanneer zij het Eisenmenger syndroom hebben.

In hoofdstuk 7 beschrijven wij de korte en langetermijn effecten van behandeling met bosentan bij zowel patiënten met als zonder het syndroom van Down. In deze studie werden 58 volwassen patiënten met PAH ten gevolge van een aangeboren hartafwijking behandeld met bosentan. Alle patiënten werden geëvalueerd voor aanvang en tijdens behandeling middels bloedonderzoek, een 6-minuten looptest, kwaliteit van leven vragen lijst en Doppler echocardiografie. Wij analyseerden het effect van behandeling bij patiënten met (n=28) en zonder (n=30) het syndroom van Down separaat. Bij patiënten met het syndroom van Down bleef de 6-minuten looptest en de kwaliteit van leven stabiel gedurende behandeling. Terwijl bij patiënten zonder het syndroom van Down de gemiddelde loopafstand in 6 minuten significant verbeterde van 427 ± 97 m tot 461 ± 104 m (p<0.01) na 6 maanden behandeling gevolgd door een geleidelijk afname en ziekte stabilisatie. Kwaliteit van leven verbeterde significant gedurende behandeling, dit effect hield aan tot 18 maanden behandeling (p<0.05).


Concluderend, konden wij door het ontbreken van gevalideerde uitkomst parameters voor patiënten met het syndroom van Down het effect van behandeling met bosentan niet aantonen bij deze patiënten populatie. Bij patiënten zonder het syndroom van Down toonden wij aan dat langetermijn behandeling met bosentan leidt tot een verbeterde kwaliteit van leven en stabilisatie van het inspanningsvermogen.

In hoofdstuk 8 bestudeerden wij de invloed van de bestaansduur van veranderingen van de pulmonale vaatwand op één jaar behandeling met bosentan bij 18 patiënten met veranderingen van de pulmonale vaatwand die gedurende het voornaamste deel van het leven al aanwezig zijn (PAH ten gevolge van een aangeboren hartafwijking) ten opzichte van 16 volwassen patiënten met subacute vaatwand veranderingen (chronisch tromboembolische pulmonale hypertensie). Alle patiënten werden geëvalueerd bij aanvang en gedurende follow-up door middel van de 6-minuten looptest en laboratorium testen. Verbetering van de 6-minuten loopafstand was vergelijkbaar in beide groepen gedurende de behandeling met bosentan. De gemiddelde 6-minuten loopafstand verbeterde significant gedurende de eerste drie maanden van behandeling en stabiliseerde in de daarop volgende negen maanden in beide groepen. Hoewel de duur van de pulmonale vaatwand veranderingen verschillend was in beide groepen was het behandel effect van bosentan vergelijkbaar. Het belangrijkste behandel effect lijkt stabilisatie van de ziekte en afname van de mate van verslechtering.

De 6-minuten looptest is een veel gebruikte primaire uitkomstmaat voor het effect van medicatie bij patiënten met PAH. Bij patiënten met ernstige PAH (WHO/NYHA III en IV) bestaat er een verband tussen veranderingen in de 6-minuten looptest en veranderingen hemodynamiek. Echter bij patiënten met een WHO/NYHA klasse II gaat significante verbetering van hemodynamica niet vergezeld van significante verbetering van de 6-minuten loopafstand. Daarom stellen wij in hoofdstuk 9 ter discussie of de 6-minuten loopafstand wel een geschikte uitkomst parameter is voor patiënten met milde PAH. We vergeleken de aerobe capaciteit gedurende maximale cardiopulmonale inspanning met de 6-minuten looptest bij 8 patiënten met een milde vorm van PAH, bij 13 patiënten met een ernstige vorm van PAH (patiënten met PAH ten gevolge van een aangeboren hartafwijking of pulmonale hypertensie ten gevolge van chronische tromboemboliën) en bij 8 gezonde controles. We lieten zien dat de 6-minuten looptest bij patiënten met een milde vorm van PAH niet overeenkomt met de maximale aerobe inspanningscapaciteit terwijl bij ernstig aangedane patiënten de 6 minuten looptest overeenkomt met de maximale aerobe inspanningscapaciteit. Wij concluderen dat de 6-minuten looptest geen geschikte maat is om het behandel effect te objectiveren bij mild aangedane patienten met PAH.

In eerder onderzoek toonden wij aan dat behandeling van pulmonale hypertensie niet bij alle patiënten resulteert in verbetering van de inspanningscapaciteit. Daarom onderzochten wij in hoofdstuk 10 of bij patiënten met PAH ten gevolge van een aangeboren hartafwijking de RV contractie duur bij aanvang een voorspeller is voor toename van de inspanningscapaciteit tijdens behandeling. Daarnaast analyseerden wij of een verkorting van de RV contractie duur tijdens behandeling geassocieerd is met een toename van inspanningscapaciteit gedurende

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behandeling met bosentan. In hoofdstuk 10 beschrijven wij de waarde van echocardiografisch gemeten rechter ventrikel (RV) contractie duur bij 9 patiënten met PAH ten gevolge van een aangeboren hartafwijking en bij 9 patiënten met chronische tromboembolische pulmonale hypertensie (CTEPH). RV contractie duur wordt gemeten van het begin van het QRS complex tot het begin van de vroege diastolische vulling van de RV (E). Een verlengde RV contractie duur leidt tot linkswaartse verplaatsing van het septum waardoor de vroege diastolische vulling van de linker ventrikel (LV) is verslechterd. In onze studie resulteerde één jaar behandeling met bosentan bij 67% van de patiënten in een verbeterde inspanningscapaciteit. Deze toename was geassocieerd met een reductie van de RV contractie duur en een afname van de linkswaardse ventrikel septum verplaatsing. Daarnaast was een RV contractie duur > 550 ms bij aanvang geassocieerd met een verbetering van de 6-minuten loopafstand (sensitiviteit 83%, specificiteit 83%; p<0.01) gedurende behandeling. Gebaseerd op deze data suggereren wij dat RV contractie duur gemeten bij aanvang gebruikt kan worden om te voorspellen welke patiënten gebaat zijn bij behandeling met bosentan.

In hoofdstuk 11 onderzochten wij of patiënten met cyanose beschermd zijn tegen het optreden van atherosclerose hiervoor maakten wij gebruik van de intima-media dikte van de carotis en inventariseerden wij riscofactoren voor het ontstaan van atherosclerose bij 54 cyanotische patiënten met een aangeboren hartafwijking en 54 leeftijd- en geslacht gematchte controles. De gemiddelde intima-media dikte, gecorrigeerd voor leeftijd was significant verlaagd in cyanotische patiënten met een aangeboren hartafwijking vergeleken met controle personen (0.55 ± 0.1 mm vs. 0.58 ± 0.08 mm) met een gemiddeld verschil van 0.04 mm (SE 0.015 mm, p=0.01). Deze afname is mogelijk het gevolg van een combinatie van verminderde atherogene risicofactoren. Bij cyanotische patiënten is het totaal cholesterol lager in combinatie met verhoogd bilirubine en verlaagde bloeddruk. Daarom suggereren wij dat in tegenstelling tot acyanotische patiënten met een aangeboren hartafwijking, atherosclerose geen extra risico vormt voor cyanotische patiënten met een aangeboren hartafwijking wanneer zij ouder worden en de leeftijd bereiken waarop atherosclerose klinisch relevant kan worden.

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Dankwoord


DankwoordAllereerst gaat mijn dank uit naar mijn promotor prof. dr. Barbara Mulder. Beste Barbara, jouw positieve instelling en motiverend vermogen is ongekend en werkt inspirerend. Mede dankzij jouw kritische blik en snelle beoordeling van mijn manuscripten, een flinke dosis humor en mooie verhalen is dit proefschrift tot stand gekomen. Bedankt voor alles wat jij mij als promotor en als mens geleerd hebt en ik hoop in de toekomst nog veel van je te mogen leren.

Mijn andere promotor prof. dr. Rolf Berger wil ik bedanken voor het grondig beoordelen van mijn manuscripten en de begeleiding van mijn promotie. Beste Rolf, vol spanning wachtte ik op de suggesties van jou, het zorgde altijd voor nuancering van het manuscript. Hartelijk dank voor de goede samenwerking.

Dr. Paul Bresser, beste Paul als co-promotor en CTEPH expert van het AMC heb jij mij veel geleerd en geïntroduceerd bij de landelijke werkgroep pulmonale hypertensie. Bedankt voor je relativeringsvermogen en de fijne samenwerking. Jammer dat je het AMC verlaat.

De overige leden van mijn promotiecommissie, prof. dr. W. Budts, dr. F.J. Meijboom, prof. dr. R.J.G. Peters, prof. dr. P.J. Sterk, prof. dr. J.G.P. Tijssen en dr. A. Vonk Noordegraaf, wil ik hartelijk bedanken voor het beoordelen van mijn proefschrift en de bereidheid zitting te nemen in mijn promotiecommissie.

Lieve Lonneke en Michiel. Ik ben heel blij dat jullie op 30 oktober naast mij staan tijdens de verdediging. Lieve Lonneke, als mede-geneeskundige van ons jaar ben jij altijd geïnteresseerd en weet jij altijd precies waar ik mee bezig ben, dat en nog veel meer waardeer ik aan je. Als ceremoniemeester op ons huwelijk was je fantastisch, gelukkig vraag ik nu niet weer zoveel van je! Lieve Michiel, onze carrière bij de cardiologie begon met de ECG-dienst. Wij hadden niet kunnen vermoeden dat we jaren later weer collega’s op B2 zouden zijn! Dagelijks even mijn hart luchten (soms al tijdens het fietsen), maar vooral het vele lachen heeft eraan bijgedragen dat wij niet alleen collega’s zijn maar ook vrienden en bovenal dat jij nu mijn paranimf bent! Daarom vind ik het net als jij heel fijn dat we altijd collega’s blijven! Lieve Lonneke en Michiel, bedankt dat jullie mijn paranimfen willen zijn.

Mijn onderzoek was niet mogelijk zonder de bereidheid van alle echo-laboranten; in het bijzonder Rianne. Bedankt voor je enthousiasme, goede ideeën en bovenal de fijne samenwerking. Daarnaast was de medewerking van de afdeling longfunctie onmisbaar. Veel dank gaat uit naar de longfunctie-assistenten en met name Maria Habes. Heel erg bedankt.

Een onderzoek als dit was niet mogelijk zonder de samenwerking met andere congenitaal cardiologen uit Nederland. Beste dr. Els Pieper en dr. Elke Hoendermis, bedankt voor alle

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informatie en hulp met het in goede banen leiden van de echo’s. Beste dr. Arie van Dijk en dr. Louise Bellersen, bij jullie op de echo- kamer voelde ik mij altijd meer dan welkom en af en toe een dagje gegevens verzamelen bij jullie was een welkome afwisseling met het AMC. Beste dr. Boonstra en dr. Vonk Noordegraaf, nogmaals bedankt dat ik jullie gegevens mocht gebruiken. Beste Thelma, ons tripje naar New York/ Philadelphia was super, jammer dat je weg bent uit het AMC. Beste Berto en Maarten, leden van de Amsterdamse congenitale club, bedankt voor jullie inbreng. Ik hoop binnenkort alles van de cardiale beeldvorming van jullie te leren.

Zonder fijne collega’s zou promotie-onderzoek voor mij onmogelijk zijn geweest. Beste Lilian, Peter en Thomas, dankzij jullie warme welkom had ik snel mijn draai binnen de “congenitale cardiologie” en op B2 gevonden. Thomas, nogmaals bedankt voor jouw IT-ondersteuning en oneindige geduld. Na jullie promotie is de “congenitale cardiologie” uitgebreid met Michiel, Jeroen en Klaartje. Ik had mij geen fijnere collega’s kunnen wensen. Top dat wij “de congenitale onderzoekers” waren! Bedankt. Maar zonder het CONCOR-team is “de congenitale” absoluut incompleet. Beste Lia, Irene, Sylvia en Enno, zonder jullie is CONCOR nergens en B2 een stuk minder gezellig. Bedankt voor de fijne samenwerking en het lachen!

Daarnaast wil ik uiteraard de andere onderzoekers die de cardiologie rijk is bedanken. Beste Margot, Niels, Joost, Jonas, Ivo, Krischan, Marcel, Maurice, Annemarie, Miranda, Anja, Xua Fei, Pieter, Christiaan, Peter, Ze-Yie, Imke en Harald, bedankt en veel succes met jullie promotie!

Onderzoekers komen en gaan op B2, zo gaat dat en dat is maar goed ook! Voor mij zijn jullie de oude garde en ik ben blij dat ik het eerste deel van mijn promotie met jullie heb gewerkt. Jacobijne, Saskia, Fons, Alexander, Marc, Pieter B, en Gerlind, ik heb stiekem veel van jullie geleerd! Nog even en dan kan ik mij weer bij jullie aansluiten, ik kijk ernaar uit!

Maar zonder Regina en Anita is de afdeling Cardiologie nergens! Bedankt voor alles!

Beste Herre, Mart en Sulaiman, bedankt voor jullie samenwerking. Het was mij een waargenoegen om met jullie, de mannen op het gebied van CTEPH, samen te werken. Beste Max, ik heb veel van je geleerd op het gebied van echocardiografie, bedankt hiervoor en succes met het verdedigen van jouw proefschrift. Verder wil ik alle andere onderzoekers op het gebied van de congenitale cardiologie en met name Laura van Loon bedanken voor de samenwerking maar vooral voor de leuke tijd.

Daarnaast wil ik de medewerkers van het ICIN bedanken voor goede samenwerking.

Lieve vriendinnen, lieve Annemieke, Monika, Pomme, Maartje, Annette, Merel en Fiore ’98! Jullie hebben geen idee hoeveel jullie voor mij betekenen. De afgelopen 5 jaar zorgden jullie

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voor de juiste balans tussen onderzoek en ontspanning. Ik hoop nog veel mooie dingen met jullie mee te maken en dat het altijd zo blijft zoals het nu is.

Lieve Pien, Michiel, Karin, Annemieke en Leander, bedankt voor al jullie interesse. Eindelijk is het dan zover, mijn proefschrift is afgerond!

Lieve Elbert, lieve broer, bedankt voor wie je bent, minstens net zo nuchter als ik! Ik ben trots op je en ben blij dat jij en Es zo dichtbij wonen! Bedankt dat jullie zeker het laatste jaar zo hebben meegeleefd en dat ik altijd bij jullie kan aanschuiven.

Lieve pap en mam, dankzij jullie eindeloos vertrouwen in mij heb ik altijd kunnen doen wat ik wil doen en ben ik geworden wie ik ben. Jullie hebben ervoor gezorgd dat ik beschik over doorzettingsvermogen en minstens net zo belangrijk relativeringsvermogen. Want het is waar, af en toe moet je ontspannen om vervolgens beter te presteren. Zonder jullie had ik dit proefschrift niet kunnen schrijven. Ik hou van jullie.

Lieve Philip, love of my life! De afgelopen jaren, van het begin tot het eind, stond jij altijd voor mij klaar. Dit was niet altijd een even gemakkelijke taak maar jij wist en weet mij altijd te motiveren. Samen zijn wij een team, door jou is dit proefschrift tot een mooi eind gekomen. Liefste, jij maakt mijn leven nog mooier, ik hou van je.

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Curriculum Vitae


Curriculum VitaeMariëlle Gea Joanna Duffels werd op 13 december 1978 geboren te Zaandam. In 1997 behaalde zij haar VWO eindexamen aan het Bertrand Russell College te Krommenie. In datzelfde jaar is zij gestart met de studie Geneeskunde aan de Universiteit van Amsterdam. De propedeuse werd in 1998 behaald, waarna de doctoraal fase in 2002 is afgerond. Sinds december 2004 is zij basisarts. Haar promotieonderzoek, zoals beschreven in dit proefschrift is aansluitend aan het artsexamen in januari 2005 gestart op de afdeling Cardiologie van het Academisch Medisch Centrum (AMC) te Amsterdam, onder leiding van prof. dr. B.J.M. Mulder, congenitaal cardioloog en prof. dr. R.M.F. Berger, kindercardioloog UMCG. Het onderzoek vond plaats in samenwerking met dr. P. Bresser, longarts AMC.

Op 1 oktober 2008 is zij gestart met de opleiding tot cardioloog, te beginnen met twee jaren vooropleiding Interne geneeskunde in het AMC (opleider: Prof. dr. P. Speelman). Hierna zal de opleiding worden vervolgd op de afdeling Cardiologie in het AMC (opleider: Dr. R.B.A. van den Brink).

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Duration of right ventricular contraction predicts the efficacy of bosentan treatment in patients...

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