Common long-term complications of - Imperial College London



Common long-term complications of adult congenital heart disease: avoid falling in a H.E.A.P.Ministeri M, Alonso-Gonzalez R, Swan L, Dimopoulos KAdult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UKNIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, UKNational Heart and Lung Institute, Imperial College School of Medicine, London, UKCorrespondence to:Dr Konstantinos Dimopoulos MD MSc PhD FESCAdult Congenital Heart Centre Royal Brompton and Harefield NHS Foundation TrustSydney Street, SW3 6NP London, UKTel+44 2073528121 ext 2771, Fax+44 207351 8629E-mail: k.dimopoulos02@Financial disclosure/Acknowledgements:Dr Dimopoulos and Dr Alonso have acted as consultants and received unrestricted education grants from Actelion, GSK and Pfizer. Dr Swan has received unrestricted educational grants from Pfizer and Actelion. Dr Ministeri has received educational grant support from the University of Catania, mon long-term complications of adult congenital heart disease: avoid falling in a H.E.A.P.SummaryAdvances in cardiology and cardiac surgery have transformed the outlook for patients with congenital heart disease (CHD) so that currently 85% of neonates with CHD survive into adult life. Although early surgery has transformed the outcome of these patients, it has not been curative. Heart failure, endocarditis, arrhythmias and pulmonary hypertension (HEAP) are the most common long term complications of adults with CHD. Adults with CHD benefit from tertiary expert care and early recognition of long-term complications and timely management are essential. However, it is as important that primary care physicians and general adult cardiologists are able to recognise the signs and symptoms of such complications, raise the alarm, referring patients early to specialist adult congenital heart disease (ACHD) care, and provide initial care.In this paper, we provide an overview of the most commonly encountered long-term complications in ACHD and describe current state of the art management as provided in tertiary specialist centres. Word count 7600 (including commentary)Keywords: congenital heart disease, adult congenital heart disease, heart failure, endocarditis, arrhythmia, pulmonary hypertension, complicationsIntroductionThe population of ACHD is rapidly expanding and ageing, with many patients well into adult life and some in the geriatric age range.1 Despite significant advances in the surgical management of patients with congenital heart disease, most surgery is still reparative rather than corrective. In several situations, only partial repair is achievable or the defect may not be repairable at all, and a definitive palliation or no intervention may be offered. Many patients, even after “total repair”, face the prospect of further operations and may often run into complications long-term. Such complications may be difficult to manage and contribute to the significant morbidity and risk of premature death described in this population. In fact, while ACHD patients with isolated simple defects have a normal life-expectancy, the mortality in certain types of ACHD (like Eisenmenger syndrome, complex congenital heart disease and Fontan physiology) may be twice to seven times higher than in the general population .2 The clinical spectrum of ACHD is obviously wide, and the risk of complications greatly depends on the underlying anomaly, previous repair and presence of residual lesions. In some patients, events that would otherwise be deemed physiological, such as pregnancy and delivery, may exacerbate symptoms and lead to significant complications. Non-cardiac intercurrent diseases, such as chest infections, traumas or conditions requiring non-cardiac surgery may also place an excessive load on patients with reduced cardiac reserve. Finally, there is an established predisposition of many ACHD patients to heart failure, endocarditis and arrhythmias, which should be monitored for and treated promptly. Unfortunately, there is little information from clinical trials to guide therapy in this growing population and management depends on good understanding of the underlying anatomy and pathophysiology and comprehensive experience of the multi-disciplinary team. Although data from patients with acquired heart disease is informative, care must be taken to examine the appropriateness of extrapolating these to patients with congenital cardiac lesions. The objective of this review is to outline the emerging evidence and experience in the management of four of the most common complications in ACHD: Heart failure, Endocarditis, Arrhythmias, and Pulmonary Hypertension (HEAP).Heart failureHeart failure (HF) is a major cause of morbidity and mortality in ACHD patients. It is defined as a combination of symptoms (e.g. dyspnea, peripheral edema) and signs (e.g., pulmonary rales, increased central venous pressure) caused by an inability of the heart to deliver a sufficient cardiac output to the organs and tissues.3 The term heart failure in ACHD includes a huge variety of patients from those with native disease (unrepaired or palliated), to those previously “repaired”. The reported incidence and prevalence of heart failure in ACHD patients depends on the definition used: an isolated rise natriuretic peptides has been described in up to 53%, while a combination of decreased exercise capacity and elevated natriuretic peptide concentration is present in 26% of this population.4,5 The hospitalization rate for symptomatic HF in ACHD has been described as 1.2 per 1000 patient-years.6 Diagnosing HF in ACHD patients may be challenging. By definition reduced exercise tolerance may be present from very early in life in ACHD patients many of whom have no experience of normal effort capacity. Furthermore, ACHD patients may be unable to detect subtle changes in their limited exercise capacity; indeed, some ACHD patients do not report significant symptoms, even those with complex congenital heart diseases and documented effort limitation. 82.4% of patients with with “single-ventricle physiology or with systemic right ventricles describe themselves as being in NYHA class I or II.7 Heart failure is a continuum, from asymptomatic cardiac dysfunction with modest neurohormonal activation, to severe symptomatic cardiac dysfunction with marked neurohormonal activation.8 Patients reporting symptoms of HF tend to have more advanced disease, with a significantly lower peak oxygen consumption on cardiopulmonary exercise testing and more impaired systemic ventricular ejection fraction compared to asymptomatic patients, as well as higher mortality. Evidence of overt clinical heart failure has been reported in 40% of patients with Fontan circulation, 32% of patients with congenitally corrected transposition of the great arteries (ccTGA) and in 22% of patients with patients with transposition of the great arteries (TGA) after atrial switch procedure (Mustard/Senning).7 In patients with repaired Tetralogy of Fallot (TOF) the cumulative incidence of heart failure at 35 years of follow-up is low (3%), despite many patients needing reoperation or developing arrhythmias.9 Patients with repaired atrio-ventricular septal defect (AVSD) show a similar trend: many require surgical reintervention for left atrioventricular valve regurgitation or other residual lesions, but the majority of patients remain in a good functional class.10 Finally patients with simple TGA after arterial switch operation present in the long term an excellent functional outcome, even though our experience is limited to 2-3 decades.11 As surgery for CHD only truly took off in the 1960s, there are limited data on the very long-term outcome of repaired patients. An increasing number of adult CHD patients present after the 5th decade of life with heart failure, especially those repaired in the earlier surgical era and/or late in their life.1The pathophysiology of HF in ACHD is multifactorial and may differ from non-congenital population. Several mechanisms contribute to HF including hemodynamic factors, such us chronic pressure and/or volume ventricular loading; electrophysiological factors such as persistent arrhythmias or long-term pacing; myocardial dysfunction due to inadequate myocardial preservation during prior surgery, longstanding cyanosis, myocardial fibrosis or diastolic dysfunction; pulmonary vascular disease; etc. Systolic dysfunction of the systemic ventricle is the rule in patients with a systemic right ventricle (Figure 1). Patients with a previous Fontan operation, on the other hand, may have preserved systolic function of the often single systemic ventricle, however, small changes in pulmonary vascular resistance will lead to failure of the Fontan circulation which might be extremely difficult to manage. Good understanding of the underlying anatomy, physiology and mechanisms responsible for the development of the HF are essential to ensure improving outcomes for these patients.As the ACHD population ages, acquired heart disease may also contribute to the development of heart failure.1 Systemic hypertension, coronary atherosclerosis, myocarditis, alcohol and diabetes mellitus can adversely impact cardiac function. The number of patients with a combination of congenital and acquired heart disease is likely to rise as the ACHD population ages. Therefore, acquired morbidities, such as coronary artery disease, seem to be key determinants of outcome in the older ACHD population, in conjunction with the underlying congenital heart disease.12Several markers have the potential of identifying ACHD patients at risk of developing heart failure, assessing disease severity and evaluating the progression of heart failure or treatment response: systolic ventricular function, diastolic ventricular function, natriuretic peptides, exercise capacity, renal dysfunction and anaemia will be key in risk stratifying these patients. Cardiopulmonary exercise testing is the best method for assessing and quantifying exercise intolerance.13–15 Interestingly, exercise capacity in ACHD patients is not directly related to resting systemic systolic ventricular function, suggesting that exercise intolerance in this cohort is indeed often multifactorial.16 Furthermore, as shown by Diller et al., cardiopulmonary exercise testing is useful in predicting morbidity and mortality.13 Peak VO2 is an independent predictor of outcome in ACHD and patients with a peak VO2< 15.5 ml/kg/min are at threefold increased risk of death and hospitalization. The VE/VCO2 slope and chronotropic response to exercise are also a strong prognostic markers of death in ACHD patients.15,17Identification of the mechanism responsible for the development of heart failure in patients with often complex anatomy and physiology is essential for their management. Echocardiography provides a wealth of information, on cardiac anatomy, haemodynamic lesions, systolic and diastolic properties of the ventricles and the pericardium. Cardiovascular magnetic resonance imaging (CMR) is being heralded as the modality of choice for the evaluation of heart function in ACHD patients.18 The right ventricle (RV) is commonly impaired in both repaired and unrepaired patients and CMR allows accurate assessment of RV volumes and hemodynamic lesions. Management guidelines for the treatment of HF in ACHD are lacking, largely due to the fact that ACHD patients are commonly excluded from HF clinical trials, and there is a paucity of data to guide therapies in this growing population. The goal of HF therapy in ACHD is similar to that in patients without ACHD: reversal of pathologic remodelling, restoration of adequate systemic/pulmonary output, and improvement/resolution of symptoms.19,20 Arrhythmias should be treated promptly and pacemaker settings optimised. Pulmonary hypertension should be identified and treated appropriately (see below). Other reversible causes of HF and precipitating factors such as ischemic heart disease, anaemia, systemic hypertension, parenchymal pulmonary disease, sleep apnoea and obesity should be sought and, when possible treated.21–23 Surgical or interventional therapyCardiac hemodynamic lesions, if present, should be the first target in the effort to improve the clinical status of ACHD patients presenting with HF. Potential therapeutic options include surgical or interventional relief of obstructive lesion, repair of valve abnormalities and elimination or reduction of the shunts. The vast majority of procedures performed on ACHD patients are reoperations. This implies an increased perioperative risk related to redo sternotomy, long bypass times and technical challenges such as calcified conduits and should be performed by experience surgeons in a specialised ACHD centre. This is particularly true for complex high-risk operations such as conversion of a failing atriopulmonary Fontan circulation to a total cavopulmonary connection (TCPC conversion). Patients with the "older version" of the Fontan circulation (atrio-pulmonary connection) over time develop severe right atrial dilation, arrhythmias, intracavitary thrombi and arrhythmia.24,25 Conversion to the more modern TCPC is a procedure that should only be performed by surgeons experienced in this operation and excludes the right atrium as well as providing more optimal haemodynamics.26 Patients with systemic right ventricle often develop severe tricuspid regurgitation, which results in ventricular overload and affects prognosis. Although tricuspid valve replacement might be indicated in this population, this should be decided and performed in a specialised ACHD centre.27 Medical therapy Diuretics are the mainstay of HF treatment in symptomatic patients, with attention on maintaining adequate preload in patients with severely impaired right ventricles and those with Fontan circulation who depend on some rise in central venous pressures to maintain pulmonary blood flow. Decompensated heart failure in patients with a “restrictive” ventricular physiology (i.e. severe diastolic dysfunction as encountered for example in elderly patients with late repair of tetralogy of Fallot) or pulmonary hypertension and concomitant renal dysfunction is particularly challenging to manage and may require prolonged hospital admissions for intravenous diuretic, with the possible addition of inotropes (e.g. dobutamine in pulmonary hypertension patients).28–31 Patients with decompensated RV failure develop significant secondary hyperaldosteronism and, therefore, spironolactone should be added to loop-diuretics in order to achieve optimal diuresis.32,33 Neurohormonal activation is common in ACHD and, despite the lack of strong evidence, many ACHD centres commonly use angiotensin-converting-enzyme inhibitor (ACE inhibitors), angiotensin receptor blockers and aldosterone antagonists in ACHD patients with heart failure.33 However, few randomized trials have been performed in this population, mostly using surrogate endpoints to evaluate the effects of drug treatment. Van der Bom et al. investigated the impact of renin-angiotensin inhibition using valsartan on systemic RV function in a randomized clinical trial that included 88 patients with systemic right ventricles.34 In their study, there was no significant treatment effect of valsartan on right ventricular ejection fraction after 3 years follow-up. However, in the subgroup analysis of the symptomatic patients, there was an improvement in RV ejection fraction of 4.5% compare to the placebo group. Furthermore, there was an improvement in RV volumes in asymptomatic patients. In the setting of repaired tetralogy of Fallot (TOF) with RV or LV dysfunction, Babu-Narayan et al. investigated in a double-blinded placebo-control trial, the impact of ramipril on RV systolic function in patients with repair TOF and moderate-severe pulmonary regurgitation.35 The study showed no difference in the primary endpoint, CMR derived RV ejection fraction (EF), as well as in long-axis function assess by echocardiography. Various small observational studies have investigated the effects of beta-blockers in different ACHD populations. Bisoprolol did not improve RV-EF in 33 patients with TOF, but resulted in an increase in natriuretic peptides level in the bisoprolol arm.36 Small uncontrolled studies suggested some beneficial effects of beta-blockade in patients with a systemic RV.37,38 The aldosterone receptor blocker epleronone resulted in a favourable change in collagen turnover biomarker profiles in patients with a systemic RV, suggesting that myocardial fibrosis might be a therapeutic target in this setting.39 Pulmonary arterial hypertension (PAH) targeted therapies are able to improve the functional status on patients with Eisenmenger syndrome (a detailed discussion of these therapies is provided in the relevant chapter). Overall the design and power of these ACHD heart failure studies makes it difficult to conclude if these therapeutic agents are of value or not. Cardiac resynchronization therapy (CRT)CRT represents another therapeutic option in ACHD patients with HF, underlying left (systemic) ventricular dysfunction and evidence of intraventricular conduction delay. Despite mounting evidence of ventricular dyssynchrony in patients with CHD, randomized trials of resynchronization in this population are lacking. The vast heterogeneity in anatomy and physiology makes identification of ideal candidates for CRT difficult. Moreover, it is still unclear whether patients with systemic right ventricles, univentricular circulation or isolated subpulmonary (right-sided) ventricular dysfunction can benefit from CRT, beyond the obvious technical difficulties in implanting such as device. Three retrospective studies of CRT in heterogeneous CHD populations have been published.40–42 Epicardial device placement was common (up to 50%). Clinical response was not uniformly defined and included improvement in EF or functional class. Using these endpoints, 32–87% of patients demonstrated improvement with CRT. However, there are still insufficient data to determine which anatomic subgroups derive the greatest benefit from CRT. According to the recently published consensus guidelines for arrhythmia management in the adult with CHD, patients with systemic LV failure and electromechanical dyssynchrony should have similar indications to non-ACHD adult CRT patients.43 Congenital or post-operative atrioventricular block with chronic RV pacing accounts for 65% of CRT implantations in ACHD subjects. Patients with systemic RV failure are those with complete TGA after atrial switch procedure, or those with congenitally corrected transposition (ccTGA). One study specifically addressed potential indications for CRT in this population.44 If the selection of candidates for CRT was based solely on NYHA class II or more symptoms in the presence of a QRS duration >120 ms, 9.3% of patients with atrial switch procedure would qualify, compared to 6.1% of those with ccTGA. In small case series of patients with systemic right ventricles, CRT has been shown to increase RV ejection fraction, decrease QRS duration, increase peak VO2, and improve functional class.42,43 However, tricuspid valve regurgitation does not appear to be significantly influenced by CRT and it is unlikely that patients with severe tricuspid regurgitation and ventricular dysfunction will benefit from CRT. The majority of patients with repaired TOF typically have a right bundle branch block (RBBB) and resultant dysynchronous contraction of the RV. However, non-ACHD patients with RBBB have demonstrated disappointing results with CRT compared to those with left bundle branch block.47 It is still unclear whether RV pacing improves RV performance in repaired TOF patients, as the QRS prolongation may be a consequence of RVOT pathology rather than the body (inlet) of the RV. There are no long- term outcome data on CRT response in adults with repaired TOF, although short-term results have shown some improvement in heart failure symptoms.48Heart transplantation Ultimately heart transplantation or heart-lung transplantation should always be considered in ACHD patients with refractory HF. In countries like Canada, transplant numbers have increased over the past two decades and the congenital lesions most commonly requiring heart transplantation are failing Fontan, Mustard/Senning procedures and congenitally corrected transposition of the great arteries.49 These patients are typically younger than other adults listed and have a lower body mass index as well as fewer comorbidities.50 Standard risk stratifiers used for listing patients for transplantation may not be applicable to ACHD. While reduced exercise performance has been associated with poor survival in ACHD overall and may prompt transplant listing, this has not been consistent across all diagnoses and cannot be depended upon. Specific risk factors to be considered are sensitization from previous transfusions, pregnancies or homograft implantations. Antibodies can persist for more than a decade after heart surgery. Elevated pulmonary vascular resistance, distorted pulmonary artery anatomy, arteriovenous fistulae and pulmonary venous hypertension require careful haemodynamic evaluation by a congenital cardiologist. Other surgical risks derive from anatomical abnormalities including abnormal position of organs or vessels (eg, situs inversus, malposition of the great arteries or venous anomalies) as well as previous cardiac operations that may add significant technical problems. Once listed, CHD patients are more likely to be listed at lower urgency (64% of CHD patients are listed as status 2 compared to 44% of non-CHD patients), despite a higher rate of complications once on the transplant list.50 This discrepancy may, in part, be explained by lower utilisation of mechanical circulatory support among CHD patients. Early post-transplant mortality is increased in patients with CHD as are post-transplant complications, including need for dialysis and prolonged intensive care unit stay. The most frequent causes of early post-transplant mortality in patients with CHD are haemorrhage and acute graft failure. Nonetheless, 10-year survival is better in CHD than in non-CHD populations. Risk factors for adverse transplant outcomes in ACHD patients include prior Fontan operation, complex anatomy, re-do sternotomy and pulmonary hypertension.Recently, given the increasing complexity of the ACHD population, and in light of advancements in the field, multi-organ transplantation may also be a consideration. In the Mayo Clinic experience of 45 patients undergoing transplant procedures (age range, 1 month to 65 years), three patients underwent successful combined-organ transplant (two heart/liver and one heart/kidney).51 Combined heart-liver transplantation may be appropriate for many patients with failing Fontan circulation, in whom a chronic raised in central venous pressure can cause significant liver derangement, cirrhosis and even hepatocellular carcinoma. More effort should be made in developing adequate criteria for referring ACHD patients to transplant. Current criteria for listing non-ACHD patients do not apply to the majority of the ACHD population, especially in those with complex cardiac anatomy and physiology. Multi-organ failure is not uncommon in patients with Fontan circulation, prohibiting heart transplantation or requiring combined heart-liver transplantation, which increases perioperative risks. Perhaps, in ACHD, the indication for referring to heart transplant should not be based primarily on functional class or exercise intolerance, but on evidence of organ failure, such as renal or liver dysfunction. The timely selection of optimal candidates remains challenging and large congenital centres need to work together to optimise transplantation outcomes in ACHD.Ventricular assist devices HF patients with CHD are more likely to have right-sided HF, pulmonary hypertension or residual shunts, which may make them less attractive candidates for ventricular assist devices (VADs).52,53 The use of VADs in ACHD patients is limited to case reports or small case series and VADs are rarely used in this population. A group of ACHD patients that is likely to benefit the most from this approach are patients with a systemic RV. The new devices are smaller overcoming the problem of inserting them in a heavily trabeculated ventricle. Peng et al., recently reported a small series of 7 patients with systemic RV failure who received the HeartWare (HeartWare International Inc, Framing- ham, MA) VAD.54 The indications was bridging to transplantation, with the aim to support the systemic RV and/or reduce pulmonary pressures. The authors showed that this third generation VAD provides durable support for the RV in both situations. With the current advances in technology, with smaller and more efficient VADs in the market, the use of VADs in the ACHD population will likely increase exponentially. In patients with single ventricle physiology and a Fontan circulation, the use of VADs is more challenging because of the need to achieve and maintain a balance between different variables, including cardiac output, ventricular load, pulmonary artery pressure and Fontan filling pressures. Despite the fact that a left-VAD could help unload the ventricle and reduce post-capillary pressures in the pulmonary circulation, the increase in cardiac output may lead to an increment in pressures in the Fontan pressures, causing hepatic and venous congestion. More data are required to understand the role of VADs in this setting.55,56Endocarditis The reported incidence of infective endocarditis (IE) in CHD is two times higher than in the general population.57 Virtually any congenital defect may predispose to the development of IE and the risk of this actually occurring is not negligible. Moreover, the risk of IE in the ACHD population is not only related to the underlying congenital defect, but also the previous surgical and percutaneous interventions, resulting in a cumulative risk for infection (Figure 2). In our experience in the ACHD population, the most common site for IE is the left ventricular outflow tract, regardless of whether previous surgery had been performed.58 Unoperated restrictive VSDs were the second most common lesion, followed by cyanotic CHD (25% of the total CHD patients with IE); TOF was the most common cyanotic condition in patients presenting with IE. Other lesions included pulmonary atresia with ventricular septal defect (VSD), single ventricular physiology, transposition of the great arteries, atrioventricular septal defect (ASD) with pulmonary stenosis, truncus arteriosus and VSD with Eisenmenger physiology. Dental or surgical procedures (especially when followed by a long stay in the intensive care unit), intravenous therapy (especially via a central intravenous catheter), cardiac diagnostic and interventional procedures, body piercing, acne and tattooing, and the insertion and delivery of intra-uterine devices are considered possible portals of entry for infections, even though strong evidence is lacking. Causative organisms are most often staphylococcal or streptococcal species, but unusual bacteria or fungi may be involved. Transcatheter (percutaneous) pulmonary valve implantation is a relatively novel therapeutic option and is currently the treatment of choice for patients with right ventricular outflow tract conduit dysfunction. Short and medium term outcomes of patients undergoing percutaneous pulmonary valve implantation appear to be good. However, some concerns have been raised with regards to the IE risk of these valves, with a reported annualized rate of 0.88%-2.4% per patient-year, possibly higher compared to homograft pulmonary valve impants.59,60The clinical manifestations of infective endocarditis are highly variable and a high level of suspicion is required to ensure timely diagnosis and treatment. The extent of local involvement of the myocardium or valves, embolization of vegetations and the activation of immunological mechanisms all play a role in defining clinical presentation. Despite the potentially devastating cardiac and systemic effects of IE, mortality related to IE has decreased substantially in ACHD to approximately 10%, much lower than in the non-congenital population. This is thanks to improvements in the diagnosis of IE, antimicrobial treatment and cardiac surgery, but also due to the fact that it affects younger people, and is often right-sided, hence, embolic or other complications have less devastating effects (e.g. destruction of the pulmonary valve).61,62 Moreover, ACHD patients with IE are most likely to be treated in tertiary ACHD centres and benefit from high levels of multidisciplinary IE expertise. IE should be suspected in all ACHD patients presenting with fever, night sweats or newly manifesting heart failure. Delayed diagnosis and referral, up to 1 month or well beyond, and inappropriate initial antibiotic therapy are common and can adversely affect the outcome. A substantial proportion (25-60%) of patients with bacterial endocarditis require elective or emergency surgery during or soon after the episode of IE in order to replace intracardiac or intravascular infected material, repair native lesions or as a result of failure of medical therapy to control the infection.61 As the diagnosis of endocarditis is often difficult, attempts have been made to establish criteria that allow for a firm (or firmer) diagnosis. Modified Duke criteria are recommended by the recent ESC Guidelines for the management of infective endocarditis, with the addition of newer imaging modalities (cardiac/whole-body CT scan, cerebral MRI, 18F-FDG PET/CT and radiolabelled leucocyte SPECT/CT), which may improve the sensitivity of these criteria, especially in difficult cases (see Table 1).63 Any imaging modality used in ACHD, especially in the setting of IE, requires very high level of expertise, in view of the complex anatomy and presence of artificial material, which can reduce the rate of detection of vegetations or other features of IE. It is recommended that all ACHD patients presenting with IE should be evaluated and managed at an early stage in an ACHD reference centre by a multidisciplinary "Endocarditis Team", including ACHD cardiologists, surgeons and anaesthetists, microbiologists and experts in ACHD imaging. Moreover, access to neurology and neurosurgical facilities is important.Medical therapy The purpose of IE treatment is to sterilize infected cardiac tissue and, by so doing, to limit the extent of damage and prevent life-threatening complications such as systemic embolism and cardiac failure. In most instances, adequate antibiotic treatment is all that is required, but in selected cases, surgery becomes necessary, sometimes early in the course of the disease. Unless the condition of the patient is deteriorating, initiation of therapy can at times be delayed until the organism has been identified and antibiotic sensitivities determined or at least until numerous blood cultures are obtained. In all instances, antibiotic treatment should never be started until an adequate number of blood cultures (at least 4) from different sites have been taken. The consensus is that bactericidal drugs should be used in preference to bacteriostatic agents and bolus intravenous injections are preferable and possibly more effective than intravenous infusions or intramuscular administration. Drug treatment of prosthetic valve endocarditis (PVE) should last longer (at least 6 weeks) than that of native valve endocarditis (2–6 weeks). PVE is the most severe form of IE and occurs in 1–6% of patients with valve prostheses. Surgical therapySurgery may become necessary during the active phase of the disease, but is associated with significant risks. However early surgery is justified when (1) medical treatment is failing, particularly when there is hemodynamic deterioration; (2) large mobile vegetation are noted on echocardiography (especially in left-sided IE); (3) a mechanical valve prosthesis is infected (by staphylococci or non-HACEK gram-negative bacteria); (4) there is evidence of an infective abscess; and (5) when fungal endocarditis is encountered.63 Prevention and antibiotic prophylaxisGiven the prognosis, morbidity and high cost of management of IE, prevention and early detection are paramount. All ACHD patients must be educated on their condition and related complications, including IE.64 This should be part of the transition program from paediatric to ACHD services and should be repeated on every consultation thereafter. When the patients are aware of the risk of IE and the possible signs and symptoms, primary prevention and early diagnosis become easier. IE prevention includes a good oral and skin hygiene. The mouth, and in particular invasive dental procedures that cause disruption of the mucosa, are felt to be a major portal of entry of organisms to the bloodstream. However, cosmetic tattooing and piercing, are also discouraged in this group. Indication for antibiotic prophylaxis are reported in the recent ESC Guidelines for the management of infective endocarditis and are limited in patients with cyanotic heart disease, those with previous IE, prosthetic valve, or prosthetic material/devices with an adjacent residual shunt or within 6 months of implantation.63ArrhythmiasACHD patients are prone to arrhythmias given the natural history of their underlying congenital heart disease (CHD), the long-standing nature of their hemodynamic alterations, and the consequences of surgical interventions. A recent study showed that, from the period 1998 to 2006, there was a 112 % increase in the number of ACHD patients that were admitted for emergency care in the United States with a diagnosis of arrhythmia.65 Bouchardy et al. reported that atrial arrhythmias occurred in 15% of adults with congenital heart disease.66 The lifetime incidence increased steadily with age and was associated with a doubling of the risk of adverse events. The presence of complex CHD, significant residual haemodynamic lesions or ventricular dysfunction, significantly increases the risk of arrhythmias, which should be treated in a timely fashion. Bradyarrhythmias The most common bradyarrhythmias seen in ACHD are sinus node dysfunction (SND) and complete heart block (CHB). SND occurs predominantly in patients who have had surgery near the sinoatrial (SA) node (Mustard and Senning operations and the various iterations of the Fontan operation). It more often appears insidiously after long-term follow-up, not only in the immediate post-operative phase. Patients with left atrial isomerism, by definition, lack a normal sinus and typically present with a low (or other) atrial or junctional rhythm. The loss of sinus rhythm could be dangerous for Fontan patients as well as patients with severely restrictive ventricles: the loss of atrial contribution significantly affects cardiac output.67 CHB is less common in the overall adult congenital population and is most commonly seen in the immediate postoperative period. However, CHB can occur spontaneously in patient with atrioventricular septal defects or ccTGA. Pacemaker implantation can be a significant endeavour in complex ACHD patients.68,69 Thorough understanding of cardiac and vessel anatomy, with particular attention to prior operative notes is essential. At times, the lack of patent peripheral veins or intracardiac anatomy itself may prohibit access to cardiac chambers, thus, requiring epicardial pacing (e.g. in Fontan patients). It is important to bear in mind that patients with transvenous pacing or defibrillators and intracardiac shunts are at risk of paradoxic emboli and, thus, anticoagulation should be considered.Supraventricular tachycardia Supraventricular tachycardia (SVT) is an important cause of morbidity for many patients with CHD. SVT mainly occurs after cardiac surgery and is often incisional atrial reentrant tachycardia (IART) related to a previous atriotomy scar. Its incidence is highest in patients who have undergone Mustard or Senning repair for d-TGA or Fontan procedure. In particular, >50% of older patients with an atriopulmonary Fontan operation develop SVTs within 10 years of repair, compared to <10% for those with the newer total cavopulmonary connection (Figure 3).70,71 Typical atrial flutter can occur in almost all forms of CHD but is most often seen in the setting of unoperated atrial septal defect (ASD) or other conditions associated with a dilated right atrium. Up to 10–25 % of patients with Ebstein’s anomaly can develop atrioventricular reentrant tachycardia (AVRT) secondary to an accessory pathway (Wolff-Parkinson-White Syndrome). SVTs is typically poorly tolerated in complex ACHD patients and acute management can be a challenge due to hemodynamic instability. As a general principle, it is important to convert patients to sinus rhythm in the most expeditious manner and a rate control strategy should be, at best, only temporary and only used in very stable patients. Synchronized electrical cardioversion is the most commonly used means for conversion to sinus rhythm in ACHD centres, under the care of experienced anaesthetists. Pharmacological therapies are less commonly used: amiodarone is probably the most used antiarrhythmic in ACHD, followed by sotalol, beta-blockers and other antiarrhythmics. Adenosine can be used but is usually inefficient with the most commonly encountered intra-atrial tachycardias. Long-term oral anticoagulation is recommended in the complex ACHD patients and SVT or atrial fibrillation, and should be considered in those with moderate forms of ACHD.43 It is unlikely that the thromboembolic risk associated with simple non valvular forms of CHD is sufficiently high to justify long-term anticoagulation as a de facto approach, such that the decision to pursue antiplatelet or anticoagulation therapy in this subgroup of patients may be guided by established non-ACHD risk scores for stroke (e.g., CHA2DS2-VASc) and bleeding risk (e.g. HAS-BLED).72 Catheter ablation has emerged as an excellent early therapeutic option in experienced ACHD centres. With standard incorporation of 3-dimensional mapping technology for precise localization of tachycardia circuits and the routine use of irrigated-tip radiofrequency ablation catheters, acute success rates of approximately 80% can be achieved.73 Late recurrence of the clinical IART or new reenty “circuits” after catheter ablation is observed in approximately one-third of patients, with higher risk in patients who have undergone the Fontan procedure.74 Ablation, when achievable and in the hands of experienced operators, is felt to be superior to long-term antiarrhythmic treatment, even if it only reduces the burden of SVT episodes. For patients with refractory IART, or if surgery is planned for hemodynamic indications, surgical ablation with an atrial MAZE procedure can be beneficial. Recurrent refractory SVT is an indication for undertaking TCPC conversion of older Fontan circuits plus right atrial Maze.20,43 Ventricular arrhythmias Sustained ventricular arrhythmia is presumed to be the most common mechanism for sudden cardiac death in the ACHD population. Ventricular tachycardia (VT) is typically encountered late after repair of TOF, but can also develop in a wide spectrum of congenital lesions. It is felt to be related to prior ventriculotomy scars or ventricular fibrosis. Non-sustained ventricular tachycardia is not uncommon in ACHD and is often completely asymptomatic, detected during ambulatory or device monitoring. For patients with documented sustained VT or cardiac arrest, definitive therapy including ICD implantation and catheter ablation, have largely replaced pharmacological management.75 All patients presenting with a VT or cardiac arrest should be investigated for coronary artery disease, on-going heamodynamic lesions, ventricular dysfunction, long-QT, RV arrhythmogenic cardiomyopathy or other syndromes predisposing to malignant arrhythmias. Invasive hemodynamic and electrophysiological evaluation may be required and there is a role, albeit limited, for VT ablation. Risk assessment for sudden cardiac death (SCD)One of the most challenging clinical problems in ACHD is the selection of patients who could benefit from primary prevention of sudden cardiac death (SCD). This needs to be weighed against the risk of Implantable Cardioverter-Defibrillator (ICD) related complications. The risk of SCD is time dependent and progressively increases after the second decade of life. Thus far, no randomized clinical trials have been performed to delineate risk factors for SCD or the benefit of primary prevention therapies in ACHD. TOF is the most carefully studied lesion with regards to VT/SCD. In adults with repaired TOF, SCD is the most common cause of late mortality, with an incidence of 2% per decade.76 However, despite numerous cohort studies that have identified factors associated with ventricular arrhythmias and sudden death, risk stratification remains imperfect. A probabilistic approach using a combination of non-invasive risk factors and programmed ventricular stimulation, as suggested by Khairy et al., may be a useful strategy to select patients at high risk who may benefit from an ICD (Table 2).77 An ICD can be problematic in young patients: beyond the need for multiple generator replacements and lead revisions, there is a significant risk of inappropriate shocks. In fact, many of these patients are likely to develop SVTs, which in great part account for the high rate of inappropriate shocks, especially in TOF patients.78 The lack of evidence on the use of ICDs in complex CHD makes clinical decision making even more difficult. Sudden death is not uncommon in these patients and implantation of an ICD may be reasonable, e.g. in adults with single ventricle physiology or a systemic right ventricle and severely reduced systemic ventricular function, especially when additional "risk factors" are present, such as complex ventricular arrhythmias, unexplained syncope, NYHA functional class III or a prolonged QRS duration >140 ms40. In patients, in whom access to the subpulmonary ventricle from the venous system is anatomically impossible, implantation of epicardial and/or subcutaneous leads is required. This is an invasive procedure, with higher lead failure rates and the possibility of developing restrictive “pericardial” physiology related to defibrillation patches.79Pulmonary HypertensionPulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (PAPm) ≥25mmHg.80 PH can be distinguished in precapillary or post-capillary, depending on whether pulmonary wedge (or left atrial) mean pressure is ≤ or >15mmHg and whether pulmonary vascular resistance exceeds (or not) 3 Wood units on right heart catheterization (RHC). It is important to distinguish between PAH-CHD and other (post-capillary) forms of PH related to CHD, as only the former benefit from targeted PAH therapies. Post-capillary PH is common in ACHD and is related to valve or myocardial disease, or pulmonary venous stenosis. Precapillary PH (pulmonary arterial hypertension, PAH) due to congenital heart disease (PAH-CHD) is also quite common and affects up to 3% of patients.81 Eisenmenger syndrome is the extreme end of the spectrum of PAH-CHD, in which there is severe pulmonary vascular disease leading to reversal of the shunt and cyanosis. A description of the various types of PAH-CHD is given on Table 3.While pulmonary vascular disease in CHD patients does not differ in terms of pulmonary histology compared with idiopathic or other types of PAH, there are important differences with regards to the pathophysiology and management. Cardiac catheterisation is essential for the diagnosis in most cases, with calculation of pulmonary vascular resistance (PVR), especially in patients with persistent L-R shunting. An exception to this rule may be Eisenmenger syndrome, in cyanotic patients with a post-tricuspid shunt (VSD or patent ductus arteriosus) in the absence of pulmonary stenosis, in whom the diagnosis may be established with a high degree of certainty by echocardiography in expert centres. In all other cases, accurate estimation of PVR, with calculation of pulmonary blood flow using the direct Fick method, is recommended.81 Surgical and interventional managementSurgical or transcatheter closure of the defect is contraindicated in all Eisenmenger patients, and those with PAH in the presence of a small defect, as the defect is felt to act as a relief valve for the right ventricle and boosts cardiac output through right-left shunting, at the expense of chronic cyanosis.82 In a subgroup of patients with L-R shunt, surgical or percutaneous repair may be indicated. Experts recommend closure of defects only when there is no significant pulmonary vascular disease (PVRi < 4Wood units × m2). When PVRi exceeds 8Wood units×m2, no intervention should be undertaken. Patients with ‘borderline’ PVRi (between 4 and 8Wood units × m2) are best assessed individually in ACHD centres.80,81Although mortality rates in PAH-CHD are frequently reported as being more favourable than those for patients with PAH of other etiology, most studies focus on Eisenmenger syndrome and follow adult survivors (i.e. a prevalent rather than incident population, see immortal time bias).83 PAH-CHD patients who have undergone corrective surgery appear to have a significantly worse prognosis than Eisenmenger patients, likely due to the lack of a "relief" valve. Medical managementIdeally, all PAH-CHD should be followed up in tertiary centres with expertise in both CHD and PAH, avoiding common pitfalls and inappropriate practices of the past, such as routine venesections in Eisenmenger patients and absolute exercise restriction. Their management is challenging and greatly based on clinical expertise rather than solid evidence, which is lacking.81 Supportive therapy includes iron supplementation, diuretics and oral anticoagulation aimed at reducing symptoms and treating or preventing complications related to chronic hypoxia, haematological and coagulation disorders, congestive cardiac failure, rhythm disturbances and infection.84 For example, simple measures such as adequate hydration, especially at the time of infections or fluid loss (diarrhoea or vomiting), are important for Eisenmenger patients, in order to avoid hyperviscosity symptoms and renal dysfunction, whilst taking care to avoid congestion. Prompt treatment of respiratory tract and other infections, early cardioversion of patients presenting with arrhythmias and good dental and skin hygiene are paramount. On the other hand, routine venesections promote iron deficiency and seem to increase rather than decrease the risk of cerebrovascular events.85,86 All non-essential surgery should be avoided when this cannot be performed under local anaesthesia, as both general anaesthesia and sedation carry significant risks in PAH-CHD. Finally, pregnancy is contraindicated in PAH-CHD, as risks remain prohibitive despite modern treatment.87,88The use of oral anticoagulants in Eisenmenger syndrome is controversial: a high incidence of pulmonary artery thrombosis and stroke is reported, but there is also an increased risk of bleeding, including potentially life-threatening haemoptysis (Figure 4).89 Given the lack of evidence, guidelines do not recommend the use of anticoagulants in PAH-CHD, but suggest they may be considered in patients with pulmonary artery thrombosis and signs of heart failure in the absence of previous significant haemoptysis.80 Nifedipine and other calcium channel blockers are contraindicated in Eisenmenger syndrome due to the risk of worsening hypoxemia through a drop in systemic compared to pulmonary vascular resistance and the subsequent increase in right-to-left shunting. Moreover, strenuous or extreme isometric efforts should be discouraged in PAH-CHD patients, but mild-to-moderate physical activity tailored to the patients’ exercise capacity and underlying cardiorespiratory physiology is recommended in order to limit the detrimental effects of physical deconditioning.90,91 Available advanced therapies (ATs) for PAH target vasoconstriction and proliferation of smooth muscle cells in the pulmonary arterial bed. To date, three identified major pathways controlling these processes have been translated into clinical practice: (a) the prostacyclin-mediated pathway, (b) the nitric oxide-mediated pathway and (c) the endothelin-mediated pathway. The widespread use of oral ATs in PAH-CHD began in 2006, after the publication of the BREATHE-5 the first randomized, double-blind, placebo-controlled trial in patients with Eisenmenger syndrome.92 In this study, bosentan (endothelin receptor antagonist) had a beneficial short-term effect on exercise capacity and cardiopulmonary hemodynamics in WHO class III patients, while demonstrating to detrimental effects on oxygen saturations. The beneficial effects of bosentan on exercise capacity were sustained up to 1 year in the open-label extension study.93 This study remains the only large Industry-led randomised controlled study in the field of PAH published to date. Subsequently, smaller studies on other drugs including Sildenafil and Tadalafil (phosphodiesterase inhibitors, acting on the nitric oxide-mediated pathway) demonstrated a significant improvement in exercise capacity and hemodynamic parameters in Eisenmenger patients.94,95 A minority of patients with PAH-CHD after repair of the defect have been included together with iPAH and connective tissue-related PAH in large randomized trials using Treprostinil, Sildenafil, and Sitaxentan (now withdrawn from the market), as well as the EARLY study demonstrating the beneficial effect of bosentan on PAH patients in functional class II.96–99 The effect of ATs on exercise capacity and functional class appears to be maintained over several years, despite some initial data suggesting loss of efficacy after the first year.100,101The prostacyclin analogue epoprostenol has been studied in the setting of PAH-CHD, showing favourable effects on haemodynamics and exercise capacity in small non-randomised cohorts.102 Concerns have been raised in relation to the risk of line infections leading to endocarditis in patients with CHD, as well as the risk of paradoxic emboli, but have not been substantiated in recent published cohorts. Limited evidence does also exist on the use of inhaled iloprost and subcutaneous treprostinil in PAH-CHD patients, which remain valid alternatives.Evidence on the use of advanced therapies in combination, sequentially or upfront, is lacking in PAH-CHD, as opposed to other types of PAH (e.g. iPAH) in which sequential and upfront combination have been shown to decrease the risk of clinical deterioration compared to monotherapy.103–105 Most PAH-CHD centres will, however, nowadays treat patients who fail monotherapy with a combination of drugs. Transplantation is the only “curative treatment” available for PAH-CHD, but is not without limitations. Lung transplantation with repair of the underlying cardiac defect or heart and lung transplantation can be performed at an acceptable risk in well selected Eisenmenger patients, resulting in an improvement in symptoms and quality of life. However, few centres can offer repair of a CHD defect at the time of transplantation, hence, requiring heart-lung transplantation. Eisenmenger patients who reach adulthood often remain clinically stable for many years or decades. By the time transplantation is considered, they are often unsuitable candidates due to established multiorgan failure (Figure 5).2,30 This, together with the chronic shortage of donors, the increased risk of perioperative bleeding and suboptimal long-term survival after heart-lung transplantation, highlight the importance of developing alternative therapies aimed at improving the quality of life and survival of these patients.Expert commentaryIn this paper, we propose an acronym to remind non-ACHD specialists of the most commonly encountered complications of ACHD. Heart failure, endocarditis, arrhythmias and pulmonary hypertension (HEAP) are not uncommon in ACHD and these patients are likely to present in local emergency and cardiac services rather than specialist hospitals. All cardiologists and emergency physicians should be equipped to acutely manage these and other complications, under the guidance of the nearest ACHD centre, and be able to promptly transfer the patients to specialist care. Established congenital networks, encompassing centres of different levels of expertise under the guidance of a tertiary specialist ACHD team, provide the best possible care for patients, whilst ensuring that local physicians are adequately supported.Key issues:The management of ACHD patients differs significantly to that of other (acquired) cardiac conditions and requires significant expertise. Specialist tertiary centres should work closely with local ACHD and general Cardiology centres to provide good care for ACHD patients as close to home as possible. A multidisciplinary approach including electrophysiology, surgeon, clinical cardiologist with experience in ACH could be the way for a good decision. All cardiologists and general physicians should be aware of the most common long-term complications encountered by ACHD patients, who are likely to present to local emergency departments. H.E.A.P. i.e. heart failure, endocarditis, arrhythmias and pulmonary hypertension are commonly encountered in ACHD and this paper provides an overview of the management of these complications for the general physician and cardiologist, who are likely to be the first to encounter these in the primary or secondary care setting.Five year view:An increasing number of adults with CHD will require expert care for long-term complications in the years to come. Advances in surgical and interventional techniques will allow us to address hemodynamic lesions and arrhythmias even more efficiently and at lower risk. New medication for pulmonary arterial hypertension will continue helping patients with severe exercise limitation, improving their quality of life and outcome. As survival improves, young patients with ever more complex disease (e.g patients with repaired hypoplastic left heart syndrome) will reach adulthood and pose significant challenges to healthcare professionals and healthcare systems. Expert tertiary centres will need to collaborate ever more closely with local cardiology services to address this challenge and provide the best possible care to this expanding population of patients.Reference annotations:Papers of special note have been highlighted as:* of interest** of considerable interestReferences1. **Tutarel O, Kempny A, Alonso-Gonzalez R, Jabbour R, Li W, Uebing A, Dimopoulos K, Swan L, Gatzoulis MA, Diller G-P. 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First large randomised trial in Eisenmenger syndrome93. **Gatzoulis MA, Beghetti M, Galiè N, Granton J, Berger RMF, 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. 2008;127:27–32. First large randomised trial in Eisenmenger syndrome: Open label extensions94. *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.e1–5. 95. *Mukhopadhyay S, Nathani S, Yusuf J, Shrimal D, Tyagi S. Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome--a randomized, placebo-controlled, double-blind crossover study. 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Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999;99:1858–1865. 103. *Galiè N, Barberà JA, Frost AE, Ghofrani H-A, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery J-L, Grünig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JHN, Langley J, Rubin LJ, AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373:834–844. 104. *Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani H-A, Jansa P, Jing Z-C, Le Brun F-O, Mehta S, Mittelholzer CM, Perchenet L, Sastry BKS, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G, SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–818. 105. *Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, S?ndergaard L. Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. Eur Heart J. 2010;31:1124–1131. 106. *Moceri P, Kempny A, Liodakis E, Alonso Gonzales R, Germanakis I, Diller G-P, Swan L, Marino PS, Wort SJ, Babu-Narayan SV, Ferrari E, Gatzoulis MA, Li W, Dimopoulos K. Physiological differences between various types of Eisenmenger syndrome and relation to outcome. Int J Cardiol. 2015;179:455–460.Table 1: Definition of IE according to the modified Duke criteria proposed by the ESC Guidelines for the management of infective endocarditis.63Major criteria1. Blood cultures positive for IEa. Typical microorganisms consistent with IE from 2 separate blood cultures: ? Viridans streptococci, Streptococcus gallolyticus (Streptococcus bovis), HACEK group, Staphylococcus aureus; ? Community-acquired enterococci, in the absence of a primary focus; b. Microorganisms consistent with IE from persistently positive blood cultures: ? ≥2 positive blood cultures of blood samples drawn >12 h apart; ? All of 3 or a majority of ≥4 separate cultures of blood (with and last samples drawn ≥1 h apart); c. Single positive blood culture for Coxiella burnetii or phase I IgG antibody titre >1:8002. Imaging positive for IEa. Echocardiogram positive for IE: ? Vegetation; ? Abscess, pseudoaneurysm, intracardiac ? Valvular perforation or aneurysm; ? New partial dehiscence of prosthetic valve.b. Abnormal activity around the site of prosthetic valve implantation detected by 18F-FDG PET/CT (only if the prosthesis was implanted for >3 months) or radiolabelled leukocytes SPECT/CT.c. Definite paravalvular lesions by cardiac CT.Minor criteria1. Predisposition such as predisposing heart condition, or injection drug use.2. Fever as temperature >38°C.3. Vascular phenomena (including those detected by imaging only): major arterial emboli, septic pulmonary infarcts, infectious (mycotic) aneurysm, intracranial haemorrhage, conjunctival haemorrhages, and Janeway’s lesions.4. Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, rheumatoid factor. 5. Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE.InterpretationDefinite IEPathological criteria ? Microorganisms demonstrated by culture or on histological examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; or ? Pathological lesions; vegetation or intracardiac abscess by histological examination showing active endocarditisClinical criteria ? 2 major criteria; or ? 1 major criterion and 3 minor criteria; or ? 5 minor criteriaPossible IE ? 1 major criterion and 1 minor criterion; or ? 3 minor criteriaRejected IE ? Firm alternate diagnosis; or ? Resolution of symptoms suggesting IE with antibiotic therapy for ≤4 days; or ? No pathological evidence of IE at surgery or autopsy, with antibiotic therapy for ≤4 days; or ? Does not meet criteria for possible IE, as aboveIE: infective endocarditis; CT: computed tomography; FDG: fluorodeoxyglucose; HACEK: Haemophilus parainfluenzae, H. aphrophilus, H. paraphrophilus, H. influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, and K. denitrificans; Ig: immunoglobulin; PET: positron emission tomography; SPECT: single photon emission computerized tomographyTable 2. Risk score for the stratification of patients with tetralogy of Fallot considered for primary prevention of sudden cardiac death (implantable cardioverter defibrillator)77VariablePoints attributed Prior palliative shunt2 Inducible sustained ventricular tachycardia2 QRS > 180 ms1 Ventriculotomy incision2 Nonsustained ventricular tachycardia2 Left ventricular end-diastolic pressure > 12 mmHg3Risk scoreRisk category 6-12High 3-5Intermediate 0-2LowTable 3. Types of PAH related to congenital heart disease80,81Group A. Eisenmenger’s syndromeIncludes all systemic-to-pulmonary shunts due to large defects leading to a severe increase in PVR and a reversed (pulmonary-to-systemic) or bidirectional shunt. Cyanosis, erythrocytosis, and multiple organ involvement are presentGroup B. PAH associated with systemic-to-pulmonary shuntsIncludes moderate to large defects; PVR is mildly to moderately increased, systemic-to-pulmonary shunting is still prevalent, whereas cyanosis at rest is not a feature. The defect could be: CorrectableNon-correctableGroup C. PAH with small/coincidental defectsIn cases with small defects (usually VSD <1 cm and ASD <2 cm of effective diameter assessed by echocardiography), the clinical picture is very similar to idiopathic PAH. Closing the defect is contraindicated. Group D. PAH after defect correction In these cases, CHD has been corrected but PAH is either still present immediately after surgery or has recurred several months or years after surgery in the absenceof significant post-operative residual congenital lesions or defects that originate as a sequelae to previous surgery. Additional types of pulmonary vascular disease related to CHDSegmental pulmonary arterial hypertension: in these cases, part of the lung vasculature develops pulmonary vascular disease, while other areas may be normally perfused or hypoperfusedRaised PVR in Fontan patients: patients with a previous Fontan-type operation can develop a rise in PVR, despite low pulmonary arterial pressurePAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; VSD: ventricular septal defect; ASD: atrial septal defect; CHD: congenital heart diseaseFigure 1: A 26 year-old patient with no previous cardiac diagnosis presents with a three-month history of progressive exertional dyspnoea. A chest x-ray shows severe cardiomegaly. On echocardiography, congenitally corrected transposition of the great arteries is diagnosed, with impaired systolic function of the dilated and hypertrophied systemic right ventricle (a) and severe tricuspid regurgitation (b). RV: right ventricle (morphological, in the systemic position); LV: left ventricle (subpulmonary); LA: left atrium; RA: right atrium; TV: tricuspid valve; MV: mitral valve.Figure 2: Septic emboli in the lungs of two patients with right-sided endocarditis. In (a), a 22 year-old patient with a restrictive perimembranous ventricular septal defect presents with general malaise for about 3 months. On echocardiography, a mobile vegetation attached to the VSD and septal leaflet of the tricuspid valve is seen. CT scan reveals several septic emboli on both lungs (arrows). In (b), CT scan of a 59-year-old man with a bicuspid aortic valve and previous Ross procedure, followed by redo pulmonary valve replacement. He is admitted for endocarditis on the pulmonary valve homograft, with an embolic abscess on the left lower lung lobe (arrow).Figure 3: A young man with a Fontan circulation for tricuspid atresia (right atrium to pulmonary artery connection) presenting with atrial fibrillation (a); the time of onset of this is unclear, likely several weeks. Despite the fact that the ventricular rate is not very fast, the echocardiogram demonstrates moderate systolic impairment of the systemic (left) ventricle. Subsequent cardiac magnetic resonance (b) and transoesophageal echocardiogram (c) show a large clot within the right atrium.Figure 4: A 36 year-old patient with complex congenital heart disease and secondary pulmonary arterial hypertension. The chest X-ray (a) shows evidence of left atrial isomerism, dextrocardia and severe dilatation of the left PA (LPA) with mural calcification (arrow). Cardiac magnetic resonance (b) shows a severely dilated LPA and right pulmonary artery (RPA), with a flap of chronic dissection in the RPA (thin grey arrow) and mural thrombus in the LPA (thick grey arrow). abFigure 5. Two very different Eisenmenger patients.106 In (a), a 34-year-old male with Down syndrome and Eisenmenger physiology secondary to complete atrioventricular septal defect. There is a large inlet ventricular septal defect (thin arrow) and a large ostium primum atrial septal defect (thick arrow) with a single atrioventricular valve. His right ventricle is hypertrophied but not significantly dilated or impaired and is well adapted to the systemic pulmonary pressures. He is stable in functional class 2 on treatment with sildenafil. In (b), a 55 year-old male with Eisenmenger physiology due to a large patent ductus arteriosus. Despite triple-combination therapy (sildenafil, macitentan and inhaled iloprost) he is in end-stage heart failure. The right ventricle is severely dilated and impaired and resembles that of patients with idiopathic pulmonary arterial hypertension. ................
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