Eisenmenger syndrome: a rare malady that continues to fascinate

This editorial refers to ‘Past and current cause-specific mortality in Eisenmenger syndrome’†, by C.M.S. Hjortshøj et al., on page 2060. Eisenmenger syndrome (ES) is very uncommon and is probably becoming even rarer over time. In this issue of the journal, Hjortshoj et al. report on outcomes in 1564 ES patients; however, this represents a 38-year cumulative experience from 13 countries across Europe, the USA, and China.1 The authors report from referral centres providing tertiary level care for large populations; but they only see ∼3–4 cases per centre per year. Furthermore, because of more successful surgeries for congenital heart diseases (CHDs) in infancy, ES is becoming rarer in developed nations; ∼8% of CHD patients had ES in the 1950s2 compared with only ∼1% of CHD patients having ES in more contemporary registries.3 Given the rarity and decreasing incidence of ES, why does it continue to fascinate cardiologists and general physicians? There are two principle reasons. First, ES patients are irreversibly ‘blue’. After millennia of evolution of our cardiorespiratory systems to ensure that Homo sapiens are ‘pink’ because their arterial blood is (nearly) fully saturated with oxygen, chronic cyanosis from young adult life is startling and unusual. This comes with its own suite of particular medical complications, with cyanosis and consequent erythrocytosis predisposing to gout, cholelithiasis, scoliosis, bleeding, and thrombosis (Figure 1). Also, ES gives us the opportunity to assess the effects of chronic hypoxaemia on every organ system. Although some organs seem relatively resilient to the effects of chronic cyanosis (kidneys, liver, and muscle), others are profoundly affected (bones, bone marrow, and skin). Of particular importance, leucocytes and other immune components are dysfunctional in the chronically cyanosed,4 , 5 probably predisposing to serious infections. Eisenmenger syndrome usually arises when a large intra or extracardiac connection, such as a Ventricular Septal Defect (as in the Figure) is left unrepaired. Initially, the blood flows from the left to the right side of the heart. Over time, the pulmonary vascular resistance can rise to exceed the systemic vascular resistance and then the flow through the defect reverses; this results in cyanosis, erythrocytosis and a variety of consequences, as shown. Secondly, ES patients have severely elevated pulmonary vascular resistance (PVR) but are peculiarly resistant to congestive right heart failure, compared with patients with high PVR but no intracardiac shunt.6 This suggests that under some circumstances, a right ventricle (RV) can cope with systemic level afterload for many decades, with hypertrophy but not failure. Probable reasons for this include that the RV never ‘detrains’ in many ES patients as the RV is not exposed to normal (low) pulmonary artery pressure in childhood. Furthermore, the intracardiac shunt provides a ‘blow off’ valve for the right heart, which can ‘decompress’, at the expense of arterial hypoxaemia. Indeed, iatrogenic creation of an atrial septal defect (by balloon atrial septostomy) has been found to be an effective palliative treatment in certain cases of severe idiopathic pulmonary hypertension.7 This ‘creation’ of acquired ES is likely to be beneficial by right heart decompression. Thus cardiovascular clinician-scientists have studied ES patients intensively, trying to understand patterns of disease, systemic effects of chronic cyanosis and erythrocytosis, and to understand adaptive mechanisms of the RV in response to high afterload. The study of ES, however, is difficult. Not only is the condition rare, but it is also very heterogeneous, with many underlying types of CHD leading to ES and with variable degrees of desaturation and compensatory erythrocytosis. Furthermore, in the absence of evidence-based guidelines specific to ES, there have been variations in treatment strategies (concerning inter alia the use of selective pulmonary vasodilator drugs and anticoagulants, or the timing and frequency of venesections). In addition, the situation is exacerbated by the expense of some of these novel drug treatments, limiting their availability, especially in developing nations. There are also substantial potential biases in studies of ES patients (particularly adults). There is a survivorship bias, an attendance bias, and selection biases for those seen at tertiary referral centres. Most studies (including that by Hjortshol et al.)1 have included both incident and prevalent cases together. Over time, as more complex lesions have yielded to paediatric surgical solutions in developed countries, later era ES patients tend to be those with the more complex congenital heart lesions, as the simpler ones have been repaired in childhood. In developing nations, however, where paediatric heart surgery is not always routinely available, ES persists; some of these patients may migrate to developed nations and attend specialist adult CHD centres there. Notwithstanding these issues that complicate the study of ES, Hjortshoj et al.1 have completed an impressively large ‘cause of death’ analysis, comprising cases seen from across the globe, over a span of nearly 40 years. There are three main messages from this study. First, the pattern of causes of death in ES has changed over time; fewer ES patients are dying now from haemoptysis, bleeding, thrombo-embolism, or peri-operative complications, and consequently a greater proportion are living long enough to die from heart failure. Infections and sudden cardiac death are the other common modes of demise in the current era. Secondly, diligent expert care in tertiary centres is likely to have had a positive impact on survival, chiefly by avoidance of high-risk situations (pregnancy, non-essential surgeries, or non-indicated venesections) and by successful treatment of certain complications (e.g. bronchial embolizations for severe haemoptysis).8 Finally, although this was not a randomized trial of ‘advanced therapies’ with selective pulmonary vasodilators, the more widespread use of these therapies in the last decade has not (yet) altered the observed pattern of causes of death in ES. In an important recent paper in the journal Circulation, a similar group of authors from the same centres as Hjortshoj et al.1 have examined 1098 ES patients seen since 2000, reporting on the predictors of death, in the last 15 years.9 Independent predictors were older age, pre-tricuspid shunt, lower oxygen saturation at rest, the presence of sinus rhythm, and the presence of pericardial effusion. The authors propose that this allows more accurate risk stratification, an important advance in managing ES patients. Eisenmenger syndrome is, therefore, a serious condition, with much premature morbidity and mortality, even in the contemporary era. Although future trials will hopefully elucidate optimal treatment strategies, our biggest challenge is to endeavour (as with smallpox and polio) to eliminate ES altogether. Early detection and successful surgical treatment can prevent ES. ES was described in the 19th century, understood in the 20th century, and ameliorated by medications in the 21st century; we can only hope that it will be nearly extinct before the 22nd century. The efforts of Hjortshoj and colleagues, with their combined multinational expertise, points to a ‘whole of world’ collaborative approach to preventing ES altogether, or at least to minimizing the potentially devastating effects of this condition. Conflict of interest: none declared.