European Heart Journal Advance Access originally published online on June 22, 2006
European Heart Journal 2006 27(14):1644-1645; doi:10.1093/eurheartj/ehi823
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Eisenmenger syndrome: towards identifying the risk factors for death
Department of Paediatric Cardiology, University Hospital of Cologne, Kerpenerstrasse 62, 50937 Cologne, Germany
* Corresponding author. Tel: +49 221 478 86301; Fax: +49 221 478 86302. E-mail address: n.sreeram{at}uni-koeln.de
This editorial refers to ‘Presentation, survival prospects and predictors of death in Eisenmenger syndrome: a combined retrospective and case–control study’
by G.-P. Diller et al., on page 1737
The first description of Eisenmenger syndrome was provided over a 100 years ago, and the concept of Eisenmenger reaction, with progressive pulmonary vascular disease and reversal of shunt as representing a final pathway for several morphological cardiac defects, is well understood.1 Given the improved awareness of congenital heart disease among paediatricians and cardiologists, the advances in imaging, surgery and intensive care facilities, and that early definitive therapy for the majority of lesions associated with a risk of developing Eisenmenger syndrome is available, a progressive decrease in the prevalence of this disease may be expected. This does not detract from the fact that a significant population of (young) adults is currently under follow-up at various centres throughout the world with this syndrome. Data from several studies suggest that their survival prospects appear to be improving (although the reasons for this are not entirely understood).2,3 Recent advances in pharmacological therapies for pulmonary hypertension and the prospect of heart–lung transplantation for selected patients emphasize the importance of correctly selecting patients for such therapies, with a view to further improving both the quality and duration of survival. It is essential, therefore, to ascertain the risk factors associated with death in this population and the actual causes of death wherever possible and to establish, if possible, a correlation between these risk factors and the ultimate cause of death. This knowledge will certainly be of relevance in optimizing the care of the individual patient.
In the majority of follow-up studies of Eisenmenger syndrome in which the cause of death was established, two distinct patterns have emerged.4–6 One subgroup appears to develop progressive heart failure, which is the cause of death, whereas a second subgroup dies suddenly. Interestingly, the relative proportion of patients dying from heart failure appears to be increasing in comparison with sudden death in the more recent studies, the reasons for which are unclear.2,3 Haemoptysis, which was the cause of death in an earlier era, remains a common cause of clinical morbidity, but not of death. The third important observation is that patients with Eisenmenger syndrome associated with complex heart disease die sooner than those with simple lesions. This may again be anticipated, given that cardiac function may be relatively well preserved for longer periods in patients with simple lesions.
From our improved understanding of the mechanisms of sudden death in young patients, either with normal hearts or with previously operated congenital heart disease, acute arrhythmia is increasingly being recognized to be the terminal event. A genetic pre-disposition (the channelopathies, arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, etc.) or congenital coronary artery abnormalities may operate in patients thought to have structurally normal hearts.7 When considering patients with previously operated heart defects, Kammeraad et al.8 performed a case–control study of sudden death in patients after a Mustard or Senning repair for transposition of the great arteries. The presence of symptoms of tachyarrhythmia, or a previously documented supraventricular tachyarrhythmia, were the best predictors of sudden death. In patients in whom an electrocardiogram was recorded during the terminal event, ventricular tachycardia or fibrillation was seen. It would be reasonable to suspect therefore that sudden deaths in the Eisenmenger population could be arrhythmic in origin. Arrhythmia (supraventricular or ventricular) may operate on its own or may produce acute worsening of cardiac performance and output, leading to death. When examining the risk factors for death in patients with Eisenmenger syndrome, it would therefore be reasonable to focus attention on factors associated with heart failure and to attempt to separate them from those which may pre-dispose to sudden arryhthmic death. This may in turn provide a clinical management algorithm that is individually tailored.
Risk factors which are associated with a failing heart are currently better understood. In the study of Diller et al.2,3 (this issue), a higher NYHA functional class and clinical and laboratory parameters of heart failure were predictors of mortality, and these observations have been borne out by earlier reports. The age at clinical presentation was also a risk factor in the study of Cantor et al.,2 and it may be presumed that younger patients have more severe disease or rapid progression. The degree of hypoxemia is also correlated with NYHA functional class, and in some studies, it was associated with a poorer prognosis, as was an elevated right atrial mean pressure, probably reflecting ventricular failure.5
What sense can however be made of the often conflicting evidence presented concerning the risk factors associated with arrhythmia or the association between a previously documented arrhythmia and sudden death? In the series of Daliento et al.,4 sudden death was the predominant mode of death (29.5% of 61 deaths). Sustained arrhythmias, supraventricular or ventricular, had been documented in 26 patients on routine electrocardiograms or 24-h Holter monitoring; however, no correlation between arrhythmias and sudden death was found. This is in contrast to more recent studies where a previously documented arrhythmia was indeed a marker for death (unfortunately, Diller et al. were unable to establish the mode of death, sudden vs. non-sudden, in their patients).2,3 What should we make of clinical symptoms suggestive of tachyarrhythmia, but without a recorded arrhythmia? Such symptoms (palpitations and syncope) appear to be relatively common. In the Mustard/Senning study, such symptoms were indeed predictive of sudden death.8 Clearcut evidence is currently unavailable for the Eisenmenger population, although in the study of Saha et al.,5 syncope was associated with a poor outcome. The electrocardiographic markers of death remain to be further elucidated. Cantor et al.2 suggested that increased precordial QRS voltages (as an index for right ventricular hypertrophy) were associated with a higher risk of death.2 As they rightly concede, however, it is unclear what this may reflect (pressure overload vs. ventricular dilation vs. altered intraventricular conduction vs. underlying complex anatomy). Diller et al. provide data to suggest that alterations in the baseline electrocardiogram, which may reflect abnormal depolarization or repolarization, could be predictors of death. It is clear from these data that patients with Eisenmenger syndrome should be aggressively monitored for diagnosis of potentially lethal arrhythmias and that symptoms of arrhythmia warrant careful follow-up with serial long-term Holter recordings. In selected cases, implantable Holter devices may also be considered. In patients with documented sustained arrhythmia, aggressive therapy with antiarrhythmia medications, pacing, or even an implantable defibrillator may be considered.
It is hoped in this way to focus on early institution of selective pulmonary vasodilator therapy for patients with increasing heart failure consequent to progression of pulmonary vascular disease, as there is some evidence that this is beneficial in the Eisenmenger population also.9,10 In patients with suspected or documented arrhythmia, arrhythmia prevention strategies should take precedence. Given the high expense involved with all such therapeutic options, such compartmentalization of management strategies, if achievable, would be of obvious benefit.
Finally, it is of interest to speculate on why survival prospects have improved for patients with Eisenmenger syndrome in the current era. Diller et al. suggest that a referral bias may be in operation, with younger patients with severe disease, and therefore earlier death being selected out from the population that normally attends a tertiary adult congenital heart disease centre. On the other hand, referral bias could also operate in a positive way, with patients with severe disease, and earlier clinical deterioration being referred sooner for expert advice and care. It is important to ask in what concrete ways has our management of Eisenmenger syndrome changed that may account for their improved survival. Improved management of pregnancies, better anaesthetic management for extracardiac operations, and improved understanding and management of the underlying haematologic abnormalities have all certainly contributed, but may not be the entire story. The mode of death in Eisenmenger syndrome also appears to have changed, with death from heart failure gaining the ascendancy compared with sudden death. This has interesting parallels with the coronary heart disease population, where liberal usage of implantable defibrillators to prevent acute arrhythmic death is improving survival and concomitantly also changing the mode of death in a similar fashion.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehl116 
References
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Related articles in EHJ:
- Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: a combined retrospective and case–control study
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