The term value in a medical context is generally understood as the ratio of benefit to cost. Thus, higher benefits and lower costs yield optimal value for any given test or intervention. Given the explosion in publications focussed on biomarkers of heart failure in recent years, one might assume that there is tremendous value in using such biomarkers in paediatric heart failure management. A careful assessment of value in this context, however, should focus less on whether a biomarker is academically interesting or shows statistically significantly differences and should focus more on whether it specifically confers benefit for children with heart failure. This requires that we examine what is known about biomarker benefits and costs in the context of paediatric heart failure patients.
A biomarker is any measurable, surrogate characteristic that reflects either the presence or absence of a disease state.Reference Nawaytou and Bernstein1 This can be a blood test, an imaging characteristic, an exercise parameter, and even a genetic profile. Serum biomarkers are particularly attractive in that their cost to the patient is relatively low in terms of money, time, risk, and ease of obtaining a sample. The potential benefits of a good biomarker are manifold (Table 1). In this review, we will primarily explore serum biomarkers of proposed utility in paediatric heart failure, especially with respect to their ability to aid clinical decision making, diagnosis, and prognosis.
Characteristics of valuable biomarkers.
The most recent adult heart failure guidelinesReference Yancy, Jessup and Bozkurt2 specifically discuss the role of three main classes of biomarkers: B-type natriuretic peptide and its more stable pro-hormone, NT-proBNP, which are markers of ventricular wall stretch; cardiac troponins – cTnI and cTnT – which are markers of myocardial injury; and markers of fibrosis, for which several manuscripts on the relatively new markers – ST2 and galectin-3 – are cited. Of these, only the natriuretic peptides have enough paediatric evidence behind them to warrant inclusion in the recently published Pediatric Heart Failure Guidelines from the International Society for Heart and Lung Transplantation (see Table 2).Reference Kirk, Dipchand and Rosenthal3
Guideline-based use of biomarkers in paediatric heart failure.
Adapted from the International Society for Heart and Lung Transplantation Pediatric Heart Failure GuidelinesReference Kirk, Dipchand and Rosenthal3
Case example: biomarkers as a diagnostic aid in paediatric heart failure
A 31-month-old boy presents to the emergency room with a 6-day history of low-grade fever and emesis. He appears dehydrated on initial examination. The patient perks up but remains tachycardic after 40 cc/kg of normal saline administration. Arrangements for admission to general paediatric service are made for presumed gastroenteritis. While waiting, several pieces of discrepant data emerge: one practitioner “thinks they heard” a soft S3 gallop, while others do not; the liver examination is documented as “normal” but is later noted to be quite enlarged; the heart size by plain film is read as “normal” but appears mildly enlarged to the emergency room resident. Troponin and B-type natriuretic peptide levels are tested and the results show elevation (cTnI 1.4 ng/dl and B-type natriuretic peptide 3500 pg/ml), prompting the emergency room team to consult the cardiology department rather than admit the patient to the general floor. The child is found to have a severe dilated cardiomyopathy and within hours requires intensive care stabilisation with inotropic support, diuretics, and 10 days of extracorporeal membrane oxygenation.
This case illustrates the ability of biomarkers to help move a patient from one diagnostic category to another. In hindsight, the diagnosis of acute decompensated heart failure is clear, but at the time of presentation the patient was initiated on a treatment pathway for sepsis with dehydration that could have ultimately caused him significant harm. The elevated troponin and B-type natriuretic peptide values did not cinch the diagnosis in isolation, however. At least one of the treating practitioners had an index of suspicion about the diagnosis that prompted her to order the biomarker tests, and those laboratory values were followed-up on and not simply discarded when they did not fit the prevailing diagnostic storyline.
The natriuretic peptides have a firmly established role in diagnosing heart failure in adults.Reference Maisel, Krishnaswamy and Nowak4–Reference Davis, Espiner and Richards8 Multiple studies in infants and children have similarly shown that B-type natriuretic peptide and its more stable pro-hormone – NT-proBNP – can be help distinguish heart failure from conditions such as lung disease, sepsis, and healthy children without heart disease.Reference Cohen, Springer and Avital9–Reference Fried, Bar-Oz and Algur11 As in our case example, B-type natriuretic peptide may be useful in triaging children with suspected heart disease in the emergency department.Reference Maher, Reed and Cuadrado12, Reference Law, Hoyer, Reller and Silberbach13 In single ventricle heart disease patients with heart failure symptoms including systemic venous congestion, B-type natriuretic peptide can also help discriminate between those with ventricular dysfunction and those with isolated cavopulmonary failure.Reference Law, Ettedgui, Beerman, Maisel and Tofovic14
As noted in the International Society for Heart and Lung Transplantation pediatric heart failure guidelines, natriuretic peptides should be used as adjunctive markers rather than as a stand-alone test in the diagnosis of heart failure in children.Reference Kirk, Dipchand and Rosenthal3 A good history, physical examination, and appropriate ancillary testing can all help point towards a diagnosis of heart failure, regardless of a child’s B-type natriuretic peptide level. A biomarker such as B-type natriuretic peptide is most helpful as a diagnostic aid when there is an intermediate pre-test probability in the mind of the practitioner who orders it. It is in this circumstance that his or her post-test probability is most likely to be properly influenced by the biomarker test results.
Case example: biomarkers as a prognostic aid in paediatric heart failure
A 13-year-old girl suffers a coronary injury during a Ross procedure for congenital aortic valve disease. Despite a coronary re-vascularisation attempt, she remains in decompensated heart failure and is cannulated onto veno-arterial extracorporeal membrane oxygenation. She shows some recovery of ventricular function by day 4, but is still quite marginal and unable to separate from extracorporeal membrane oxygenation. Her initial B-type natriuretic peptide of 2500 pg/ml decreases to 1500 pg/ml with extracorporeal membrane oxygenation cannulation, but subsequently trends up with a value of 4000 pg/ml at day 4 of support. A suitable donor heart becomes available and the decision is made to proceed with heart transplantation rather than waiting in the hopes of further myocardial recovery.
In this case, B-type natriuretic peptide was used as a prognostic aid, which helped to guide clinical decision making. A small case series from Taiwan suggested such prognostic value of B-type natriuretic peptide when used in children on and recently weaned from extracorporeal membrane oxygenation.Reference Huang, Wu and Ko15 The prognostic utility of B-type natriuretic peptide has been satisfactorily demonstrated in the case of children after all stages of single ventricle palliation.Reference Lowenthal, Camacho and Lowenthal16 Likewise, B-type natriuretic peptide and NT-BNP have been found to correlate with outcomes in children with chronic left ventricular systolic dysfunction with a variety of underlying cardiomyopathies.Reference Price, Thomas and Grenier17 Similarly, a post-hoc analysis of the Pediatric Carvedilol Trial showed that B-type natriuretic peptide predicted outcomes in children over 2 years of age with moderately symptomatic heart failure.Reference Auerbach, Richmond and Lamour18
As with diagnosis, the ISHLT pediatric heart failure guidelines give a category IIb nod to the use of natriuretic peptides in describing prognosis.Reference Kirk, Dipchand and Rosenthal3 A recent review on the use of natriuretic peptides in CHD reminds us that the literature supporting the use of these markers in children is encouraging, but comes from relatively small studies in heterogeneous populations.Reference Cantinotti, Law and Vittorini19 The holy grail, of course, for a prognostic biomarker in paediatric heart failure is that which predicts patients who will or will not recover to a compensated state. If one could identify those who will need long-term advanced heart failure therapies up front, this could facilitate in making decisions regarding the timing of mechanical circulatory support and listing for heart transplantation.
Troponin has been best validated in paediatrics for its role in the diagnosis of myocarditis.Reference Soongswang, Durongpisitkul and Nana20 Interestingly, this same marker has not been consistently shown to predict outcomes in children with myocarditis, whereas B-type natriuretic peptide and several imaging parameters – for example, ejection fraction by echocardiogram and late gadolinium enhancement by cardiac MRI – are predictive of poor outcomes.Reference Sachdeva, Song, Dham, Heath and DeBiasi21 Troponin has, on the other hand, been shown to be predictive of outcome in scenarios including post-congenital heart surgery extracorporeal membrane oxygenation.Reference Ruffer, Munch and Potapov22 It has yet to be demonstrated whether the newer, highly sensitive troponin assays will yield prognostic value in paediatrics as they have in adult heart failure.Reference Latini, Masson and Anand23–Reference Pascual-Figal, Casas and Ordonez-Llanos25
Caution should be exercised in the interpretation of a biomarker because their normal values may vary widely by age, in addition to their variation by assay and laboratory.Reference Cantinotti, Law and Vittorini19 In addition, proper validation of any novel biomarker may be costly and time prohibitive.Reference Rifai, Gillette and Carr26 Fortunately, the reference ranges for several heart failure biomarkers have at least been explored in children. Neonates (<7 days old) in the Better Not Pout study were found to have a higher B-type natriuretic peptide cut-off value for detecting significant heart disease compared with older children (140 versus 41 pg/ml).Reference Law, Hoyer, Reller and Silberbach13 Interestingly, newborns may also show elevations in troponins not seen in older children, even when otherwise healthy.Reference Lipshultz, Simbre and Hart27 The normal values for newer markers ST2 and galectin-3, in contrast, do not appear to differ significantly between children and adults.Reference Meeusen, Johnson and Gray28
Future steps in paediatric heart failure biomarker investigation will almost certainly involve a multimarker approach. Such a strategy has been shown in adults to provide better risk stratification than relying on a single biomarker alone,Reference Ky, French and Levy29, Reference Richter, Koller and Hohensinner30 and it also provides the opportunity to improve our understanding of the underlying biology of disease when biomarkers along several different pathophysiological pathways are explored.Reference Braunwald31 As new generation biomarkers of heart failure emerge, cross-sectional cohorts of children can be approached for hypothesis-generating research in conjunction with exploration of other imaging markers such as strain and strain rate by echocardiogram as well as T1 mapping by cardiac MRI. Longitudinal, often collaborative, studies should follow suit in order to demonstrate the correlation between these biomarkers with relevant intermediate- and long-term outcomes, as well as to determine what additive benefit these markers yield above otherwise standard clinical assessments.
In summary, the B-type natriuretic peptides – B-type natriuretic peptide and NT-proBNP – appear to be useful in supporting a diagnosis of heart failure when the differential is broad. The cardiac troponins – cTnI and cTnT – and natriuretic peptides may also have some prognostic value in paediatric heart failure, although the clinical utility of such information is supported largely by small, non-randomised studies. Further studies are needed to determine the clinical utility of ST2, galectin-3, and other novel biomarkers in paediatric heart failure. The value of any of these biomarkers for children with heart failure will be maximised when its results have the potential to positively affect clinical decision making, and thus clinical outcomes.
Acknowledgement
None.
Financial Support
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Conflicts of Interest
None.
