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Model of chronic adaptation: right ventricular function in Eisenmenger syndrome

Gerhard-Paul Diller^1,2, Konstantinos Dimopoulos^1,2, Henryk Kafka³, Siew Yen Ho⁴ and Michael A. Gatzoulis^1,2,*

¹ Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
² National Heart and Lung Institute, Imperial College, London, UK
³ Division of Cardiology, Queen’s University Cardiovascular Laboratory, Kingston General Hospital, Kingston, ON, Canada
⁴ Cardiac Morphology, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK

^* Corresponding author. Tel: +44 20 73518602; fax: +44 20 73518629. E-mail address: m.gatzoulis{at}rbh.nthames.nhs.uk

	Abstract

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
Pulmonary arterial hypertension (PAH) is commonly associated with adult congenital heart disease. Eisenmenger syndrome—severe pulmonary hypertension with shunt reversal and cyanosis—represents the extreme manifestation of PAH in patients with congenital heart disease and has become the epitome of PAH in this setting. Despite representing a multi-system disorder and being associated with numerous complications, survival prospects for patients with Eisenmenger syndrome are superior compared with patients with idiopathic pulmonary hypertension. We review aetiology, clinical presentation, and prognosis of Eisenmenger syndrome and discuss potential explanations for the remarkable resilience of the right ventricle in this setting.

Key Words: Pulmonary arterial hypertension • Eisenmenger syndrome • Right ventricular function

	Introduction

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
It has been estimated that approximately 5–10% of patients with congenital heart disease develop pulmonary arterial hypertension (PAH).^1–3 Eisenmenger syndrome represents the extreme manifestation of PAH in this setting and has become the epitome of severe PAH associated with congenital heart disease.^4,5 The prevalence of Eisenmenger syndrome among contemporary adult congenital heart disease patients under follow-up at tertiary centres in Europe and North America is estimated at 4%.⁶ Improved awareness of and timely operations in current practice are likely to lead to a reduction in future numbers of Eisenmenger patients. Once Eisenmenger syndrome has developed, however, closure of the underlying heart defect is contraindicated and can precipitate death. Traditionally, therapeutic options for patients with Eisenmenger syndrome were limited to palliative measures; the mainstay of care has been not to destabilize the delicate balance between systemic and pulmonary blood flow.⁷ Heart and lung transplantation represents a treatment option for highly selected patients and has the potential to improve quality of life.^8,9 Recently, new drugs for the therapy of PAH have become available,^10–13 and some of these therapies have also been applied to Eisenmenger patients, with encouraging preliminary results.^14,15

Despite comparable morbidity, survival prospects for Eisenmenger patients are far superior compared with patients with idiopathic PAH.¹⁶ In contrast to idiopathic PAH—a condition with devastating short-term prognosis¹⁷—survival prospects are clearly better in patients with Eisenmenger syndrome.^16,18–20 Survival rates of 75, 70, and 55% at 30, 40, and 55 years of age, respectively, have been reported in contemporary Eisenmenger cohorts.²⁰

It is largely unclear why Eisenmenger patients fare so much better compared with patients with other forms of PAH despite similar pulmonary haemodynamics and histopathologies. It has been postulated that ‘the integrity of right ventricular function, rather than the degree of vascular injury, ... is the major determinant of symptoms and survival in pulmonary arterial hypertension’.²¹ We present a description of the patient with Eisenmenger physiology, with particular emphasis on the remarkably resilient right ventricle in this setting.

	Survival and risk stratification

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
Several studies have consistently demonstrated that despite being a multi-system disorder with considerable morbidity, survival prospects are much better than previously thought and superior compared with patients with idiopathic or other forms of PAH. We have recently reported a contemporary cohort of 171 Eisenmenger patients followed up at our tertiary centre with a 5 year survival rate of 88%.¹⁸ This is in clear contrast to patients with idiopathic PAH who have a devastating short-term prognosis and a reported median survival of 2.8 years,¹⁷ although before the advent of advanced medical therapies.

Hopkins et al.¹⁶ compared directly the survival prospects of Eisenmenger patients with patients with idiopathic PAH. Patients with Eisenmenger syndrome had a more favourable outcome with a 3 year event-free survival rate of 80% compared with <30% in patients with idiopathic PAH.

Despite relatively low annual mortality rates, life expectancy is significantly reduced in Eisenmenger patients compared with the normal population, however (Figure 1).¹⁸ Predictors of mortality in this population include low functional class, clinical signs of heart failure, a history of clinical arrhythmia, elevated right atrial pressure, evidence of right ventricular hypertrophy or repolarization abnormalities on the electrocardiogram, elevated levels of uric acid, complex underlying cardiac anatomy, and Down’s syndrome.^{18–20,22–25} Moreover, Somerville²⁶ reported that right ventricular failure and sudden cardiac death are the leading causes of mortality in this population. Preservation of right ventricular function appears, therefore, to be a major determinant of survival in Eisenmenger patients.

View larger version (10K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Survival prospects of patients with Eisenmenger physiology when compared with an age- and gender-matched healthy population showing reduced life expectancy in patients with Eisenmenger syndrome. Reproduced with permission from Diller et al.18

 

	Central role of right ventricular function in Eisenmenger syndrome

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
The response of the right ventricle to PAH varies significantly according to aetiology and rate of disease progression. Rapid right ventricular dilatation and deterioration of systolic function occur in patients with idiopathic PAH or PAH to pulmonary or connective tissue disease. Right ventricular dysfunction is thought to be a major contributing factor to the adverse prognosis in this setting.²⁷ Deterioration of right ventricular function, in contrast, is much slower in Eisenmenger patients.²⁸ Hopkins²⁹ postulated that this phenomenon may be explained by the preservation of a foetal-like phenotype in Eisenmenger patients with post-tricuspid defects. The authors provide data to suggest that right and left ventricular morphologies remain constant in Eisenmenger patients of various ages and are similar to those observed during foetal life. It appears, therefore, that the normal regression of right ventricular hypertrophy during the first months of life does not occur in Eisenmenger patients, and a foetal phenotype is maintained throughout life (Figure 2). This phenotype appears to be better suited to sustain elevated right ventricular afterload over a long period of time. Moreover, the right ventricle of patients with PAH associated with congenital heart disease is exposed to high pressures from infancy and may, therefore, be ‘trained’ to sustain systemic pulmonary pressures, reducing the incidence of early right ventricular failure.

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 Relationship between the left and the right ventricular wall thickness in foetuses, infants, and adults with Eisenmenger syndrome, illustrating the preservation of a foetal-like phenotype in Eisenmenger patients with post-tricuspid defects. Reproduced from Hopkins et al.60 (with kind permission from Elsevier).

 
Little is known about myocardial perfusion in the right ventricle of patients with PAH. Similar to left ventricular hypertrophy, hypertrophy of the right ventricle is expected to result in impaired right ventricular compliance and a reduction in relative myocardial perfusion.³⁰ In left ventricular pressure overload, a disproportionate increase in ventricular mass compared with vascular growth, extrinsic compression, and vascular dysfunction lead to a decrease in coronary flow reserve.³¹ Increased angiogenesis, although with reduced capillary density and reduced maximal coronary vasodilator capacity, has been described in animal models of right ventricular hypertrophy.^32–34 Capillary rarefaction was nevertheless found to be more prominent in adult compared with younger individuals with left ventricular hypertrophy.^35,36 In analogy, right ventricular hypertrophy that develops in infancy or never regresses after birth could also be associated with preserved myocardial perfusion and thus a lower risk of developing ventricular dilatation and dysfunction. Unfortunately, to date, data in this regard are lacking and the physiology of a chronically pressure-overloaded right ventricle in the presence of a large ventricular communication is poorly understood.

The pathophysiological changes described earlier only seem to apply to patients with defects distal to the tricuspid valve (such as ventricular septal defects, truncus arteriosus, aortopulmonary window, and persistent ductus arteriosus).²⁹ In some patients with PAH secondary to large interatrial communications, the right ventricle tends to dilate and deteriorate more rapidly. Survival from the time advanced PAH is established in these patients may be comparable with that of patients with idiopathic PAH. To this point, it has been often debated whether such patients have Eisenmenger syndrome or idiopathic PAH in the presence of an atrial septal defect. Compared with patients with post-tricuspid shunts, PAH among patients with atrial septal defects occurs, in general, much later in life.^1,22 It can, thus, be postulated that loss of right ventricular hypertrophy during infancy, lack of a training effect on the right ventricle during childhood, and the absence of a ventricular communication that pairs the two ventricles functionally might contribute to this difference in right ventricular response between these distinct two groups.

	Relationship between right ventricular function and exercise capacity in Eisenmenger patients

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
Patients with Eisenmenger syndrome are extremely limited in their functional capacity. We have recently demonstrated that PAH and cyanosis are strong correlates of exercise intolerance in patients with congenital heart disease.³⁷ Perhaps not surprisingly, the combination of the two, as in patients with Eisenmenger physiology, severely limits exercise tolerance. Indeed, patients with Eisenmenger physiology were the most limited among stable adult congenital heart disease patients, with an average peak oxygen uptake of 11.5 mL/kg/min, a degree of exercise intolerance comparable with that seen in patients with idiopathic PAH.³⁷

There are, however, important prognostic and pathophysiological differences between these groups. Although the prognostic value of poor exercise capacity is well established in idiopathic PAH patients,³⁸ low exercise capacity appears not to carry prognostic information in patients with Eisenmenger syndrome.^39–41 It has been postulated that early termination of exercise in Eisenmenger patients may be related to an increase in right-to-left shunting and arterial hypoxaemia, rather than to ominous pathophysiological abnormalities with prognostic implication such as poor ventricular function, autonomic nervous dysfunction, or myocardial ischaemia. Furthermore, it seems that Eisenmenger syndrome is associated with abnormalities such as systemic endothelial dysfunction, and these factors may confound the prognostic value of exercise capacity in Eisenmenger patients.⁴² As a consequence, the prognostic value of peak oxygen consumption in patients with Eisenmenger syndrome is limited, at best. It may be that the 6 min walk test is more suitable for the routine outpatient assessment of these patients, providing information on their overall cardiovascular status, disease progression, and response to therapy. This is speculative, however, and more work in this area is required.

In individuals with a normal pulmonary vascular bed, blood flow through the lungs increases at the beginning of exercise thanks to a sudden drop in pulmonary vascular resistance.⁴³ In contrast, pulmonary resistance is fixed in patients with advanced pulmonary vascular disease. Eisenmenger patients are, thus, unable to increase their cardiac output through an increase in pulmonary blood flow, but do so by a progressive increment in right-to-left shunting at the expense of cyanosis.⁴⁴ The occurrence of right-to-left shunting could suggest that right ventricular afterload is in part relieved by the presence of the intracardiac defect and could be another contributing factor to the relative preservation of right ventricular function compared with patients with idiopathic PAH.

	Interventricular interdependence in Eisenmenger syndrome

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
Interventricular interdependence plays a key role in defining cardiac output in patients with idiopathic PAH and acts in numerous ways. Left ventricular filling and consequently systemic cardiac output can be affected by reduced pulmonary venous return. Increased right ventricular pressure results in deviation of the ventricular septum towards the left ventricle (the characteristic D-shaped left ventricle) and a reduction in the left ventricular capacitance. A different and less detrimental form of interventricular interdependence seems to occur in the presence of a large interventricular communication and equalization of pressures between the right and left ventricles. In this setting, the two ventricles act as a single entity throughout the cardiac cycle. In fact, a linear relation has been found between the right and left ventricular mass and function in Eisenmenger patients.^29,45

	Assessment of right ventricular function

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
Objective quantification of right ventricular function is inherently difficult due to complex anatomy and dependence on loading conditions.^30,46

Cardiovascular magnetic resonance imaging (CMR), with its advantages of a wide field of view, no anatomic plane restriction, and superior reproducibility, has been established as the gold standard for the assessment of right ventricular volume, mass, and function. This has made it the tool of choice for the assessment of the right ventricle in congenital heart disease⁴⁷ and PAH,⁴⁸ as well as to assess the possible causes (pulmonary thrombosis, congenital heart disease) and consequences (pulmonary artery dilatation and biventricular remodelling)⁴⁹ of PAH. Although a number of CMR imaging-based methods for measuring pulmonary arterial pressure have been advocated,⁵⁰ there is no consensus on their validity.⁵¹ Nevertheless, techniques combining CMR imaging and invasive pressure monitoring have been developed and evaluated to assess the measurement of pulmonary arterial compliance.⁵² The clinical relevance of these techniques remains to be determined, however.

The differences described in the right ventricular configuration for the patients with PAH, with and without congenital heart disease,^21,29 can be further appreciated with CMR imaging. Figure 3 demonstrates a lesser degree of right ventricular dilatation and a lack of reverse septal curvature in a patient with Eisenmenger syndrome compared with an age-related patient with idiopathic PAH. These observations fit in well with those made by echocardiography to help explain the better clinical outcome of the Eisenmenger patient.²⁹

View larger version (159K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 3 End-diastolic and end-systolic cardiac magnetic resonance images from a patient with idiopathic pulmonary hypertension (A and B) and from an Eisenmenger patient with persistent ductus arteriosus (C and D). The right ventricle in the patient with idiopathic pulmonary hypertension is dilated at end-diastole, and the septum curves leftwards at early diastole. In the Eisenmenger patient, the interventricular septum maintains its rightward curvature throughout diastole and systole.

 
CMR imaging with late gadolinium enhancement has been used to demonstrate the presence of fibrosis in the pressure-loaded systemic right ventricles of patients with transposition of the great arteries after Senning or Mustard repair.⁵³ Furthermore, such right ventricular, late gadolinium enhancement has been correlated with markers of adverse clinical events in tetralogy of Fallot.⁵⁴ Similarly, the presence of fibrosis would be expected in the pressure-loaded ventricles of patients with PAH or Eisenmenger syndrome. Although there have been observations of late gadolinium enhancement in these patients (Figure 4), to date there has been no published systematic analysis of late gadolinium enhancement in patients with Eisenmenger in comparison with those with idiopathic PAH. Blyth et al.⁵⁵ did demonstrate late gadolinium enhancement in 23 of 25 patients with PAH and concluded that the degree of enhancement correlated with right ventricular function and septal bowing. The pattern of late gadolinium enhancement in their patients always involved the superior and inferior insertion points, and in 16 patients, extended further into the interventricular septum. Unlike the patients with a systemic right ventricle or with tetralogy of Fallot, patients with PAH showed no late gadolinium enhancement elsewhere in the right ventricle. Although late gadolinium enhancement may be promising as a marker of fibrotic change in both these groups, its exact role in the long-term management of these patients remains to be determined. The presence of fibrotic changes in the right ventricle in patients with Eisenmenger syndrome has also been suggested by post-mortem examinations. The right ventricle is commonly enlarged and has a thick wall ranging from 0.8 to 2.5 cm thickness in a small series recorded at the Royal Brompton Hospital, London (S.Y.H., personal communication). In some cases, white streaks of fibrosis can be seen on cut surface of the wall as illustrated in Figure 5. On microscopy, myocyte hypertrophy with patchy fibrosis is commonly seen. Fibrotic patches may be extensive, becoming occasionally transmural. Interstitial fibrosis can be widespread with islands of degenerate myocytes surrounded by a lace-like arrangement of fibrous tissue. Similar histological changes have been described in the right ventricles with muscular obstruction to outflow.⁵⁶

View larger version (75K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 4 Cardiac magnetic resonance images from the same two patients as Figure 3 showing late gadolinium enhancement. Areas of late gadolinium enhancement appear white in contrast to the normal myocardium which appears black. Both patients demonstrated late gadolinium enhancement at the superior and inferior right ventricle insertion points. This pattern has been described previously in patients with systemic right ventricle and tetralogy of Fallot and appears to have no clinical significance in those patients.8,9 Recently, extension of late gadolinium enhancement into the interventricular septum has been reported as correlating with right ventricular dysfunction and septal bowing in a group of patients with pulmonary hypertension.55 The long-term clinical significance of late gadolinium enhancement in patients with pulmonary hypertension and in those with Eisenmenger syndrome remains to be demonstrated.

 

View larger version (106K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 5 (A) A heart from a 33-year-old female showing hypertrophy and patchy fibrosis of the right ventricular wall. (B) This transmural section stained with Masson’s trichrome stain shows fibrous tissue in green and myocardium in red. (C) Close-up shows interstitial fibrosis surrounding islands of myocardium (x100). VSD=ventricular septal defect.

 
Even though CMR is the investigation of choice for the assessment of the right ventricle, echocardiographic markers of right ventricular function are helpful in the routine follow-up of such patients. Measures of the longitudinal contractility such as M-mode tricuspid annulus displacement and tissue Doppler parameters are especially useful in assessing the right ventricular systolic function. In contrast to the left ventricle which ejects a significant proportion of its stroke volume as a result of torsional shape changes, the right ventricular stroke volume grossly depends on the longitudinal shortening.⁵⁷ The deeper right ventricular muscle fibres are, in fact, predominantly arranged in a longitudinal fashion from the tricuspid valve annulus to the apex.⁵⁸ Thus, the longitudinal tricuspid annular motion and velocity closely reflect the right ventricular free wall function. In our experience, the right ventricular long-axis function is usually preserved or mildly impaired in patients with Eisenmenger physiology, in contrast to patients with idiopathic PAH, in which right ventricular function becomes impaired soon after the establishment of severe PAH. In the latter group, right ventricular dysfunction is generally accompanied by significant right ventricular dilatation. Figure 6 shows 2D and long-axis M-mode echocardiograms from a patient with Eisenmenger physiology and a patient with idiopathic PAH, illustrating right ventricular dilatation and impaired longitudinal function in the latter and preserved right ventricular function in the former. Again, to date, no large study has systematically compared the longitudinal right ventricular function in patients with idiopathic PAH and those with PAH ‘associated’ with congenital heart disease.

View larger version (113K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 6 Impaired tricuspid annular plane systolic excursion in a patient with idiopathic pulmonary hypertension (left upper panel). This is in contrast to preserved right ventricular long-axis function in a patient with Eisenmenger physiology (right upper panel). There is a different degree of right ventricular dilatation and hypertrophy on the 2D echocardiography in the individuals with idiopathic pulmonary hypertension (left lower panel) or Eisenmenger physiology (right lower panel), respectively.

 
Although emphasis in this series has been placed on new imaging modalities, the role of clinical examination,⁷ ECG, chest radiography,⁵⁹ and transthoracic echocardiography should not be underestimated.⁶⁰ They are routinely and easily performed, providing essential data on heart rhythm, early cardiovascular decompensation, changes in cardiothoracic ratio, overall biventricular function, and atrial dimensions, all of which contribute to prognosis and management.

	Conclusion

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
Patients with Eisenmenger syndrome present with unique and challenging pathophysiology. Maintained right ventricular function is a common and key feature enabling superior long-term survival in this patient population compared with other patient groups with PAH. The mechanisms underlying preserved right ventricular function over decades in Eisenmenger patients are poorly understood, however. Further studies with imaging, such as cardiac MRI and tissue Doppler echocardiography, and with potential surrogate markers for right ventricular function such as brain natriuretic peptide, the 6 min walk test, and autonomic nervous activity are clearly warranted.

	Acknowledgements

Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 
G.-P.D. was supported in part by an educational grant from Actelion, UK. M.A.G. and the Royal Brompton Adult Congenital Heart Centre have received support from the Clinical Research Committee and the British Heart Foundation. K.D. received support from the European Society of Cardiology. Professor Gatzoulis received unrestricted educational grants from Actelion and Pfizer, UK and has served on the advisory board of both.

Conflict of interest: none declared.

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Top Abstract Introduction Survival and risk stratification Central role of right... Relationship between right... Interventricular interdependence... Assessment of right ventricular... Conclusion Acknowledgements References

 

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