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Biomarkers in congenital heart disease

The population of adults with congenital heart disease (CHD) now exceeds the population of children with CHD. The long-term management of these patients relies on sequential assessment of anatomy and physiology and integration with symptoms, all targeted toward decision making around intervention. The advances in technology have vastly improved our assessment of anatomy and function. However, while the assessment of chronic heart failure in acquired heart disease has been revolutionized by the proven utility of cardiac biomarkers, their use in adult CHD is still being assessed.

Richard Dobson1, Hamish A Walker1 & Niki L Walker*,1 Scottish Adult Congenital Cardiac Service, West of Scotland Heart & Lung Centre, Golden Jubilee National Hospital, Clydebank, G81 4DY, UK *Author for correspondence: [email protected] nhs.net 1

Keywords:  adult congenital heart disease • biomarkers • heart failure • heart function

The success of pediatric cardiology and cardiac surgery has resulted in an increasing population of adults with congenital heart disease (CHD). In all but the most simple lesions, interventions in childhood are rarely curative, necessitating lifelong follow-up for many. Further interventions, whether surgical, transcatheter or pharmacological, are inevitable for many patients in order to ­preserve cardiac function. The challenge for the team caring of these adults is the timing of intervention. No patient wishes to take medications unless absolutely necessary and side effects may impact significantly on quality of life. Premature surgical reintervention at worst exposes the patient to unnecessary risk, particularly in a time when technical advances are ever increasing the range of transcatheter solutions. Furthermore, for many patients who require repeated interventions, early surgery may increase the total number of surgeries during their life. Not only does this expose the patient to the risk of an extra intervention, but risk also increases with each surgery. While transcatheter intervention has lessened the requirement for surgery in some cases, procedures are still associated with significant risk and inappropriate treatment is unacceptable. Conversely, late intervention may allow

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permanent damage to cardiac function and a reduced benefit from treatment. Sequential follow-up aims to integrate information gained from clinical review, noninvasive imaging and/or invasive hemodynamic assessments in an attempt to determine the optimal timing of intervention. International guidelines have been agreed based on the available evidence helping to guide management. However, in contrast to many areas of acquired cardiology practice, these guidelines are based on expert consensus rather than high-quality evidence from randomized trials. The utility of biomarkers in acquired structural heart disease is well established. Clinically relevant biomarkers have been required to be clinically available, contributing new information, and that information aids in the management of the individual patient [1] . Biomarkers offer the potential for a novel approach to the assessment of cardiac function in adult CHD (ACHD) either directly or through the consequences of a changing cardiac status on other organ systems. The utility of biomarkers in the assessment of ACHD has yet to be realized, with small studies only offering a glimpse of the true potential to monitor disease and inform on the timing of interventions.

Biomarkers Med. (2014) 8(7), 965–975

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Review  Dobson, Walker & Walker The ultimate biomarker, or combination of biomarkers, in monitoring cardiac function in ACHD has yet to be described. The current paper summarizes the available evidence and gives a clear indication of the need for further research into this field. Method We searched Ovid Medline including in-process and other nonindexed citations from 1947 to January 2014 week 1, and Embase from 1996 to January 2014 week 2. Subheadings used included ‘Biological Markers and Heart Defects, Congenital’ (Medline), and ‘Biological Marker’ and ‘Congenital Heart Disease’ (Embase). Keyword searches were also employed for each database. Finally, we manually searched the reference lists of key review articles. We excluded papers that assessed the use of biomarkers exclusively in a perioperative setting, or that employed them for prenatal screening of CHD. Results Natriuretic peptides Description

Three natriuretic peptides have been identified, namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). ANP and BNP are released from cardiac myocytes in both the atria and ventricles in response to shear stress due to conditions causing pressure or volume loading of the cardiac chambers, and both have been studied with respect to CHD. In each case, a propeptide is cleaved to the biologically active peptide and also an inactive amino or ‘N’-terminal peptide fragment. Thus, potentially four different natriuretic peptides can be measured: the biologically active ANP and BNP, and the inactive NT-proANP and NT-proBNP [2] . The N-terminal peptides have a longer half life in vivo and therefore give a potentially more accurate indication of cardiac wall stress [3] . CNP is considered as a neuropeptide that is primarily distributed in the CNS. It is also produced in the kidney and can be measured in the urine. There is early interest in the clinical utility of CNP as a biomarker in acute decompensated heart failure, highlighting the renal insult of decompensated heart failure as part of the cardiorenal syndrome [4] . Natriuretic peptides are elevated in CHD

Elevated mean levels of the natriuretic peptides in cohorts of patients with CHD are well described. Bolger and colleagues assessed ANP and BNP levels in 53 patients with a variety of CHD diagnoses and demonstrated significantly elevated levels compared with controls [5] . This was confirmed in a number of larger studies assessing ANP, BNP and NT proBNP levels in CHD [6–11] .

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Other studies have assessed whether natriuretic ­peptide levels are elevated in specific CHD diagnoses. Patients with a volume-loaded right ventricle (RV), typically as exemplified by repaired tetralogy of Fallot (ToF) with free pulmonary regurgitation, have raised BNP or NT proBNP levels [8,12–15] . This appears to be the case even in small cohort studies of less than 50 patients, and has been confirmed in a recent ­meta-analysis of 770 patients [16] . Patients with a pressure-loaded RV also have elevated natriuretic peptide levels compared with healthy controls. The most common model for the pressure loaded is the systemic RV, which is most often associated with congenitally corrected transposition of the great arteries or atrial switch surgery for complete transposition of the great arteries. Three studies have demonstrated elevated BNP levels [6,17,18] , two studies have demonstrated elevated ANP and BNP levels [19,20] , and one study has demonstrated elevated NT proBNP levels [21] . In cyanotic CHD, or pulmonary arterial hypertension resulting from CHD (PAH-CHD), studies have confirmed raised BNP and NT proBNP levels [22–25] . A single meta-analysis suggests that patients with these diagnoses are likely to have the highest BNP and NT proBNP levels in comparison to other forms of CHD [26] . In patients with a Fontan circulation, the findings are more ambiguous. In a large pediatric study (patient age range: 6–18 years) of 510 patients with both atriopulmonary Fontan and total cavopulmonary connection (TCPC), the median BNP level was low at 13 pg/ml. However, patients with AP rather than TCPC Fontan, evidence of ventricular dysfunction or who had developed Fontan complications such as thrombosis were more likely to have elevated BNP levels [27] . In a cohort of 66 patients with TCPC, only a third had NT proBNP levels above the upper limit of normal [28] . A subsequent study from the same center, this time of 124 patients with AP or TCPC Fontan circulations, demonstrated that elevated NT proBNP levels were more likely in the case of an AP Fontan [29] . In a smaller cohort of 50 patients with a mean age of 22.7 years, both ANP and BNP levels were significantly elevated in comparison to healthy controls [30] . A single study of a small cohort of 26 patients with Ebstein anomaly showed elevated BNP levels compared with 19 healthy controls, although interestingly BNP levels did not correlate with echocardiographic assessment of the severity of the lesion [31] . Two studies assessing natriuretic peptide levels in coarctation of the aorta (CoA) were identified. One small study of only 19 adult patients with repaired CoA found that NT proBNP levels were not elevated compared with controls [32] . Conversely, a larger study of

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Biomarkers in congenital heart disease 

74 adult patients found that levels of BNP were elevated compared with controls [33] . In congenital aortic stenosis (AS), BNP levels were not significantly elevated compared with controls, even in the presence of a peak aortic valve gradient of up to 105 mmHg [34] . This is in contrast to larger studies of patients with acquired AS where natriuretic peptide levels are typically elevated, although even then it should be noted that correlation with markers of lesion severity is at best modest [35] . Finally, some studies have assessed natriuretic peptide levels in the presence of a hemodynamically significant atrial septal defect (ASD) or ventricular septal defect. As with Fontan patients levels may not always be elevated in comparison to age- and sex-matched controls, however they are much more likely to be so in the presence of pulmonary arterial hypertension or a significant shunt [36–39] . The recent paper by Eindhoven and colleagues [26] has elegantly demonstrated the correlation of NT proBNP with a range of congenital cardiac lesions in the adult population. As demonstrated in Figure 1 from [26] , the impact of a systemic RV or univentricular physiology are reflected in elevation of NT proBNP levels. However, as the authors conclude, further work is required to understand the prognostic implications of elevations in the NT proBNP level. Correlation of natriuretic peptides with other markers of clinical status in ACHD Functional status

A number of studies assessed the relationship between natriuretic peptide levels and New York Heart Association (NYHA) class. Most of these demonstrated a positive correlation between ANP, BNP or NT proBNP levels and NYHA class [5,7,11,13,40,41] . However, it should be noted that in the Tutarel paper, NT proBNP levels were not significantly different between NYHA class II and III, and in one admittedly small study of 18 patients with Eisenmenger syndrome there was no relationship with NYHA class at all [24,41] . NYHA class is a subjective measure of functional capacity, and in clinical practice it can sometimes be difficult to discriminate between the different classes. Formal exercise testing provides a more objective measure of assessment in this regard, and forms a major part of the follow-up of more complicated patients with ACHD [42,43] . The relationship between levels of the natriuretic peptides and parameters derived from cardiopulmonary exercise testing has been assessed in a number of studies. The largest comprised 265 patients with a variety of CHD diagnoses, and showed an inverse correlation between BNP level and peak oxygen uptake (VO2), and a positive correlation with the minute ven-

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tilation and carbon dioxide output (VE/VCO2) ratio [44] . Both of these markers have prognostic value in ACHD and can predict hospitalization or death [45,46] . Most of the other studies have also confirmed that higher natriuretic peptide levels are associated with lower peak oxygen uptake [5,11,41] , although some smaller studies and those assessing natriuretic peptide levels in Fontan patients have not [20,30,31,40] . One study of 50 patients with repaired toF showed an inverse correlation between NT proBNP levels and peak oxygen uptake, but no correlation with NT proANP levels [8] . Noninvasive imaging assessment of cardiac function & lesion severity

Several studies have assessed the relationship between natriuretic peptides and parameters assessed by echocardiography and MRI. In patients with repaired ToF, echocardiographic measurements of ventricular dilatation as defined by RV end-diastolic dimension or the RV to left ventricle diameter ratio correlate directly with levels of BNP and NT proBNP [16,47] . Formal RV ejection fraction is difficult to measure via 2D transthoracic echocardiography in CHD owing to the abnormal morphology of the chamber in certain lesions. Reduced myocardial performance index or AV valve annulus longitudinal velocity may be more reproducible ways of quantifying RV systolic function, and appear to correlate reasonably well with BNP ­levels [17,48] . Where cardiac MRI is available, RV volumes and ejection fraction can be assessed with a high degree of accuracy and reproducibility. A positive correlation with BNP and NT proBNP levels has been demonstrated in systemic RV, ASD and repaired ToF cohorts [14,21,49,50] . One small study of 50 patients with repaired ToF suggested a relationship between NT proBNP levels and the degree of RV fibrosis present, as assessed by scoring for late gadolinium enhancement [51] . In patients with a Fontan circulation, there was a weak correlation between BNP levels and systemic ­ventricular mass [27] . Regarding valve function, higher BNP levels have been noted in the presence of significant tricuspid or pulmonary regurgitation in repaired ToF [13,52] , and NT proBNP levels are weakly correlated with the degree of systemic ventricular atrioventricular regurgitation in patients post-TCPC [29] . In congenital AS, BNP levels have not been demonstrated to correlate with lesion severity [34] . Two small studies of patients with an unrepaired ASD or ventricular septal defect have shown a positive correlation between BNP and shunt size, as assessed by Qp:Qs on transthoracic echocardiography [37,53] .

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Review  Dobson, Walker & Walker Invasive assessment of cardiac function

The relationship between natriuretic peptides and data from cardiac catheterization studies is less well ­characterized owing to the small study size. Elevated end diastolic pressure appeared to be most consistently associated with elevated natriuretic peptide levels in a wide range of pathologies [7,50,54,55] . One study of 16 repaired ToF patients employed a conductance catheter to identify early onset of RV dysfunction by measuring RV end-systolic pressure volume relation as a marker for contractile reserve. Unfortunately, BNP levels correlated only weakly with this [56] . Prognostic value of elevated natriuretic peptides in ACHD

Perhaps one of the most valuable applications of natriuretic peptide assays in patients with acquired heart failure has been that of risk stratification; identifying patients with a poorer prognosis. Unfortunately this has not been well characterized in CHD due to relatively small cohort sizes and the limited length of follow-up of most of these studies. One study of 49 adult CHD patients with a median follow-up of 7.9 years demonstrated that ANP and BNP levels were strongly predictive of mortality. A BNP value >78 pg/ml predicted death with 100% sensitivity and 76% specificity, and an ANP value of >146 pg/ml predicted death with a 73% sensitivity and 95% specificity. However, almost one in five patients had moderate-to-severe systemic ventricular dysfunction, so this cohort may not be representative of most ACHD populations [57] . In a cohort of 383 patients with a variety of congenital cardiac diagnoses, BNP levels were predictive of morbidity in a multivariate model in the subgroup of 82 patients with a Fontan circulation, with a hazard ratio of 1.08 (95% CI: 1.03–1.13) for every 10-pg/ml increase in BNP [58] . Two studies of patients with Eisenmenger syndrome have also shown that BNP levels are predictive of hospitalization or death. The largest study of 181 patients with a median follow-up of 3.3 years demonstrated a hazard ratio for mortality of 1.68 for every 100-pg/ml increase in BNP [59] . A serum BNP level of >140 pg/ ml or rapid increase in BNP over time was predictive of hospitalization with heart failure or death in a smaller study of 53 patients [60] . Utility of natriuretic peptide assays in predicting response to a medical or surgical intervention

In acquired heart failure, serial measurements of natriuretic peptides can be used to assess response to therapy, and in valvular heart disease there is increasing interest in the role of natriuretic peptides in identifying

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patients who would benefit from surgical intervention [35,61] . Once again, this has yet to be well demonstrated in CHD. Medical therapy

Only three studies were identified that assess the response of natriuretic peptide levels to medical treatment for heart failure. Each study comprised less than 50 patients, and in all cases the affected ventricle was morphologically an RV. One study of Olmesartan in 41 repaired ToF patients with moderate-to-severe pulmonary regurgitation showed a small reduction in BNP levels after 6 months of treatment; however, this was not correlated to any other outcome measures [62] . A randomized controlled trial of 26 patients with a systemic RV failed to show a significant reduction in NT proBNP with administration of Eplerenone for 1 year; however, as well as the small size, the mean RV ejection fraction at baseline was actually preserved at 55% [63] . Finally, the administration of Losartan in a randomized controlled crossover trial to 29 patients with a systemic RV and impaired RV ejection fraction at baseline (mean 42%) failed to show any significant reduction in NT proBNP or exercise capacity after 15 weeks of treatment [64] . Surgical & device therapy

One of the most common interventions performed in adult CHD is pulmonary valve replacement (PVR) for the severe pulmonary regurgitation that results from ToF repair or congenital pulmonary stenosis treatment in childhood. Three studies comprising a total of 70 patients have assessed trends in natriuretic peptides following PVR (60 surgical, ten percutaneous), and all demonstrated a significant fall in BNP or NT proBNP after the intervention [65–67] . Unfortunately, the studies have been too small to identify a cutoff at which PVR is associated with better clinical outcomes. Natriuretic peptide levels have also been assessed in response to ASD device closure. In the largest study of 446 patients undergoing this procedure, there was an initial rise in ANP and BNP levels, and this only subsequently fell at 6 months in the younger patients (

Biomarkers in congenital heart disease.

The population of adults with congenital heart disease (CHD) now exceeds the population of children with CHD. The long-term management of these patien...
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