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Biomarkers in pediatric heart disease
A biomarker is a characteristic that can be used as an indicator of a biological state. A biomarker can be a clinical observation, laboratory test or an imaging parameter. In this review, we discuss the use of biomarkers in differentiating cardiac from noncardiac disease; predicting the prognosis of patients with heart failure, pulmonary hypertension and dilated cardiomyopathy; diagnosing subclinical cardiac involvement in muscular dystrophy and postchemotherapy cancer patients; detecting acute rejection following heart transplantation; diagnosing Kawasaki disease; aiding the management of postoperative cardiac patients; and managing both common (tetralogy of Fallot) and complex (single-ventricle physiology) congenital heart diseases. Keywords: biomarker • cardiomyopathy • cardiotoxicity • congenital heart disease • heart failure • heart transplant • Kawasaki disease • natriuretic peptides • postoperative • pulmonary hypertension
A biomarker is a measurable, surrogate characteristic that reflects the presence or severity of a disease state. A good clinical biomarker is one that is readily available, easily measurable, and is sensitive and specific to the disease state it is intended to measure. Preferably, the biomarker would vary with varying severity of the disease. Broadly defined, a biomarker can be a clinical observation, laboratory test or imaging parameter. In the field of pediatric cardiology there is a specific need for developing clinical biomarkers, since many pediatric patients cannot express their symptoms precisely, and the symptoms and signs of heart disease may overlap with these of other organ dysfunction [1] . Children with myocarditis often present with flu-like symptoms and infants with known heart disease and deteriorating myocardial function commonly present with noncardiac symptoms such as irritability, respiratory distress or gastrointestinal upset. It is often difficult for the clinician to differentiate on clinical grounds between early cardiac decompensation and intercurrent illnesses; available
10.2217/BMM.14.37 © 2014 Future Medicine Ltd
Hythem Nawaytou1 & Harold S Bernstein*,2,3 Department of Pediatrics, University of California, San Francisco, CA, USA 2 The Mindich Child Health & Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 3 Merck Research Laboratories, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA *Author for correspondence: harold.bernstein@ merck.com 1
diagnostic tests are either labor intensive or expensive. In this article, we will describe the use of biomarkers in certain clinical scenarios for which they have shown utility in children and adolescents. Biomarkers can help differentiate between cardiac and noncardiac causes of symptoms – for example, respiratory distress and syncope – in guiding management of heart failure and of postcardiac surgery patients; and in differentiating patients with Kawasaki disease from patients with other causes of skin rash. We will also discuss how available biomarkers can guide management of patients with cardiomyopathy, pulmonary hypertension, postural orthostatic tachycardia syndrome, cardiac transplantation, tetralogy of Fallot (TOF) and single-ventricle physiology. Cardiac vs noncardiac disease Biochemical biomarkers
Natriuretic peptides are used in adults to differentiate between pulmonary and cardiac causes of dyspnea. These are hormones that play a role in intravascular sodium and water
Biomarkers Med. (2014) 8(7), 943–963
part of
ISSN 1752-0363
943
Review Nawaytou & Bernstein homeostasis, and the regulation of vascular tone. They also have antifibrotic functions. B-type natriuretic peptide (BNP) has emerged as one of the most useful biomarkers in pediatric heart disease. The peptide is secreted as a prohormone in response to ventricular wall stress and then cleaved into two polypeptide fragments; the active component BNP and the inactive fragment N-terminal ProBNP (NT-proBNP). Both components have been used as biomarkers of heart disease. NT-proBNP has a longer half-life and hence higher levels with fewer fluctuations over time. BNP can be used in the diagnosis of heart disease in children. Many studies have shown its usefulness in differentiating pulmonary from cardiac disease in children presenting with respiratory symptoms (Table 1) . In one study, a BNP ≥40 pg/ml had an accuracy of 84% in differentiating cardiac from pulmonary disease [2] . BNP levels were higher in patients with ventricular dysfunction than in patients with chronic volume overload [2] . Law et al. established that a cut point of 40 pg/ml was able to differentiate children with heart disease from those without [3] . As BNP levels are markedly elevated in the early neonatal period, the same study showed that a BNP ≥170 pg/ml had 94% sensitivity and 73% specificity for detecting the presence of heart disease in the neonate. Another study looked at BNP levels within the neonatal period, and showed that cut point BNP values for identifying patients with heart disease varied by the patient’s age in hours during the first 3 days of life [4] . Similar studies have been performed with NT-proBNP [5] . However, different cardiac lesions have different effects on BNP level. Koch et al. showed that BNP lev-
els are elevated in patients with ventricular dysfunction and volume overload, mildly elevated in aortic stenosis, but not elevated in coarctation of the aorta, pulmonary stenosis or TOF. BNP did not correlate with ventricular hypertrophy [6] . Thus, the pediatric heart may better compensate for pressure overload than volume overload, or may use different compensatory mechanisms with different effects on BNP secretion. This was shown in a study of repaired TOF patients in which the patients with pulmonary valve incompetence had BNP levels five- to ten-times the levels in patients with isolated pulmonary stenosis. Patients with pulmonary incompetence had significantly lower left ventricular ejection fraction (LVEF), but on linear regression analysis the right ventricular corrected ejection fraction was an independent predictor of BNP level [7] . This is further substantiated by the finding of decreasing BNP levels in patients who develop Eisenmenger physiology [8] . A normal BNP level does not rule out heart disease but reflects a compensated cardiac status, such that serial measurement of BNP levels in cardiac patients can provide an early warning for myocardial decompensation. In neonates presenting with respiratory distress, BNP can differentiate between patients with and without persistent pulmonary hypertension of the newborn (PPHN). In neonates with PPHN, BNP remains elevated during the first 4 days of life. This elevation correlates with the degree of pulmonary hypertension measured by Doppler echocardiography [9] . BNP [10] and NT Pro-BNP [11] can also be used in differentiating premature infants with and without a patent ductus arteriosus, and its decline with therapy
Table 1. Usefulness of natriuretic peptides in differentiating cardiac from noncardiac disease. Study (year)
No. patients Age
Design inclusion/exclusion criteria
Results
Koulori et al. (2004)
49
Mean 29.7 ± 59.3 months
Prospective study/inclusion: patients presenting with acute respiratory distress; exclusion: patients with known chronic lung disease, renal disease, single-ventricle physiology, prematurity 10. However, BNP levels did not correlate well with patient symptoms [18] . Patients suffering from pulmonary arterial hypertension (PAH) may present with syncope, an ominous sign, and can run a silent course before becoming symptomatic. Natriuretic peptide levels have only weak-to-moderate correlation with functional state [19,20] , 6-min walk distance [19] , echocardiographic [20,21] and invasive hemodynamic measurements [19,21] . BNP trend over time, however, is a better biomarker for progressive disease [21] . BNP is not a good predictor of mortality, especially in patients with associated congenital heart disease [20] . Recently, quantification of circulating endothelial cells has been explored as a biomarker for predicting reversibility of PAH associated with congenital heart disease. Proliferative, apoptosis-resistant endothelial cells have been observed in surgical lung biopsy samples from patients with irreversible PAH due to congenital heart disease [22] . Smadja et al. showed that >10 circulating endothelial cells per milliliter has a negative-predictive value of 100% and a positive-predictive
future science group
Review
value of 83.3% for irreversible PAH [23] . Patients with idiopathic/familial pulmonary hypertension who carry a mutation in the BMPR2 gene tend to exhibit poor response during vasodilator testing [24] , suggesting a poor response to calcium channel blocker therapy [25] . Biomarkers have also been used to predict response to treatment in patients with POTS. The pathophysiology of POTS is complex and includes hypovolemia, autonomic dysregulation, accentuated adrenergic resp onse and impaired endothelial function. Midodrine, an α-adrenergic agonist, has 70% efficacy [26] in alleviating symptoms of POTS, likely through its vasoconstrictor effect. Patients with elevated midregional proadrenomedullin [27] , a surrogate of adrenomedullin, or elevated erythrocytic hydrogen sulfide [28] , showed good response to midodrine. Imaging biomarkers
Response to midodrine in POTS patients can be predicted by other tests. Brachial artery flow-mediated vasodilation >9.5% at baseline was predictive of clinical response to midodrine with 70% sensitivity and 80% specificity [29] . However, a decrease or no change in systolic blood pressure upon standing, or a decrease, no change, or increase
Biomarkers in pediatric heart disease
A biomarker is a characteristic that can be used as an indicator of a biological state. A biomarker can be a clinical observation, laboratory test or an imaging parameter. In this review, we discuss the use of biomarkers in differentiating cardiac from noncardiac disease; predicting the prognosis of patients with heart failure, pulmonary hypertension and dilated cardiomyopathy; diagnosing subclinical cardiac involvement in muscular dystrophy and postchemotherapy cancer patients; detecting acute rejection following heart transplantation; diagnosing Kawasaki disease; aiding the management of postoperative cardiac patients; and managing both common (tetralogy of Fallot) and complex (single-ventricle physiology) congenital heart diseases. Keywords: biomarker • cardiomyopathy • cardiotoxicity • congenital heart disease • heart failure • heart transplant • Kawasaki disease • natriuretic peptides • postoperative • pulmonary hypertension
A biomarker is a measurable, surrogate characteristic that reflects the presence or severity of a disease state. A good clinical biomarker is one that is readily available, easily measurable, and is sensitive and specific to the disease state it is intended to measure. Preferably, the biomarker would vary with varying severity of the disease. Broadly defined, a biomarker can be a clinical observation, laboratory test or imaging parameter. In the field of pediatric cardiology there is a specific need for developing clinical biomarkers, since many pediatric patients cannot express their symptoms precisely, and the symptoms and signs of heart disease may overlap with these of other organ dysfunction [1] . Children with myocarditis often present with flu-like symptoms and infants with known heart disease and deteriorating myocardial function commonly present with noncardiac symptoms such as irritability, respiratory distress or gastrointestinal upset. It is often difficult for the clinician to differentiate on clinical grounds between early cardiac decompensation and intercurrent illnesses; available
10.2217/BMM.14.37 © 2014 Future Medicine Ltd
Hythem Nawaytou1 & Harold S Bernstein*,2,3 Department of Pediatrics, University of California, San Francisco, CA, USA 2 The Mindich Child Health & Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 3 Merck Research Laboratories, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA *Author for correspondence: harold.bernstein@ merck.com 1
diagnostic tests are either labor intensive or expensive. In this article, we will describe the use of biomarkers in certain clinical scenarios for which they have shown utility in children and adolescents. Biomarkers can help differentiate between cardiac and noncardiac causes of symptoms – for example, respiratory distress and syncope – in guiding management of heart failure and of postcardiac surgery patients; and in differentiating patients with Kawasaki disease from patients with other causes of skin rash. We will also discuss how available biomarkers can guide management of patients with cardiomyopathy, pulmonary hypertension, postural orthostatic tachycardia syndrome, cardiac transplantation, tetralogy of Fallot (TOF) and single-ventricle physiology. Cardiac vs noncardiac disease Biochemical biomarkers
Natriuretic peptides are used in adults to differentiate between pulmonary and cardiac causes of dyspnea. These are hormones that play a role in intravascular sodium and water
Biomarkers Med. (2014) 8(7), 943–963
part of
ISSN 1752-0363
943
Review Nawaytou & Bernstein homeostasis, and the regulation of vascular tone. They also have antifibrotic functions. B-type natriuretic peptide (BNP) has emerged as one of the most useful biomarkers in pediatric heart disease. The peptide is secreted as a prohormone in response to ventricular wall stress and then cleaved into two polypeptide fragments; the active component BNP and the inactive fragment N-terminal ProBNP (NT-proBNP). Both components have been used as biomarkers of heart disease. NT-proBNP has a longer half-life and hence higher levels with fewer fluctuations over time. BNP can be used in the diagnosis of heart disease in children. Many studies have shown its usefulness in differentiating pulmonary from cardiac disease in children presenting with respiratory symptoms (Table 1) . In one study, a BNP ≥40 pg/ml had an accuracy of 84% in differentiating cardiac from pulmonary disease [2] . BNP levels were higher in patients with ventricular dysfunction than in patients with chronic volume overload [2] . Law et al. established that a cut point of 40 pg/ml was able to differentiate children with heart disease from those without [3] . As BNP levels are markedly elevated in the early neonatal period, the same study showed that a BNP ≥170 pg/ml had 94% sensitivity and 73% specificity for detecting the presence of heart disease in the neonate. Another study looked at BNP levels within the neonatal period, and showed that cut point BNP values for identifying patients with heart disease varied by the patient’s age in hours during the first 3 days of life [4] . Similar studies have been performed with NT-proBNP [5] . However, different cardiac lesions have different effects on BNP level. Koch et al. showed that BNP lev-
els are elevated in patients with ventricular dysfunction and volume overload, mildly elevated in aortic stenosis, but not elevated in coarctation of the aorta, pulmonary stenosis or TOF. BNP did not correlate with ventricular hypertrophy [6] . Thus, the pediatric heart may better compensate for pressure overload than volume overload, or may use different compensatory mechanisms with different effects on BNP secretion. This was shown in a study of repaired TOF patients in which the patients with pulmonary valve incompetence had BNP levels five- to ten-times the levels in patients with isolated pulmonary stenosis. Patients with pulmonary incompetence had significantly lower left ventricular ejection fraction (LVEF), but on linear regression analysis the right ventricular corrected ejection fraction was an independent predictor of BNP level [7] . This is further substantiated by the finding of decreasing BNP levels in patients who develop Eisenmenger physiology [8] . A normal BNP level does not rule out heart disease but reflects a compensated cardiac status, such that serial measurement of BNP levels in cardiac patients can provide an early warning for myocardial decompensation. In neonates presenting with respiratory distress, BNP can differentiate between patients with and without persistent pulmonary hypertension of the newborn (PPHN). In neonates with PPHN, BNP remains elevated during the first 4 days of life. This elevation correlates with the degree of pulmonary hypertension measured by Doppler echocardiography [9] . BNP [10] and NT Pro-BNP [11] can also be used in differentiating premature infants with and without a patent ductus arteriosus, and its decline with therapy
Table 1. Usefulness of natriuretic peptides in differentiating cardiac from noncardiac disease. Study (year)
No. patients Age
Design inclusion/exclusion criteria
Results
Koulori et al. (2004)
49
Mean 29.7 ± 59.3 months
Prospective study/inclusion: patients presenting with acute respiratory distress; exclusion: patients with known chronic lung disease, renal disease, single-ventricle physiology, prematurity 10. However, BNP levels did not correlate well with patient symptoms [18] . Patients suffering from pulmonary arterial hypertension (PAH) may present with syncope, an ominous sign, and can run a silent course before becoming symptomatic. Natriuretic peptide levels have only weak-to-moderate correlation with functional state [19,20] , 6-min walk distance [19] , echocardiographic [20,21] and invasive hemodynamic measurements [19,21] . BNP trend over time, however, is a better biomarker for progressive disease [21] . BNP is not a good predictor of mortality, especially in patients with associated congenital heart disease [20] . Recently, quantification of circulating endothelial cells has been explored as a biomarker for predicting reversibility of PAH associated with congenital heart disease. Proliferative, apoptosis-resistant endothelial cells have been observed in surgical lung biopsy samples from patients with irreversible PAH due to congenital heart disease [22] . Smadja et al. showed that >10 circulating endothelial cells per milliliter has a negative-predictive value of 100% and a positive-predictive
future science group
Review
value of 83.3% for irreversible PAH [23] . Patients with idiopathic/familial pulmonary hypertension who carry a mutation in the BMPR2 gene tend to exhibit poor response during vasodilator testing [24] , suggesting a poor response to calcium channel blocker therapy [25] . Biomarkers have also been used to predict response to treatment in patients with POTS. The pathophysiology of POTS is complex and includes hypovolemia, autonomic dysregulation, accentuated adrenergic resp onse and impaired endothelial function. Midodrine, an α-adrenergic agonist, has 70% efficacy [26] in alleviating symptoms of POTS, likely through its vasoconstrictor effect. Patients with elevated midregional proadrenomedullin [27] , a surrogate of adrenomedullin, or elevated erythrocytic hydrogen sulfide [28] , showed good response to midodrine. Imaging biomarkers
Response to midodrine in POTS patients can be predicted by other tests. Brachial artery flow-mediated vasodilation >9.5% at baseline was predictive of clinical response to midodrine with 70% sensitivity and 80% specificity [29] . However, a decrease or no change in systolic blood pressure upon standing, or a decrease, no change, or increase
