**5. Cardiac biomarkers**

Congenital heart disease or defect (CHD) is the most common birth defect in newborns [51]. Critical CHDs require intervention or surgery in the first year of life. Echocardiography is a definitive diagnostic tool of CHD and provides hemodynamic and anatomic information of heart. Twenty‐five to 30% of children, however, with critical CHD are not detected by fetal echocardiography until after discharge from the birth hospitalization [52]. Cardiac biomarkers are essential to evaluate heart function and give information of myocardial injury, necrosis, or myocardial stretch. Concentrations of cardiac troponins, troponin I (TnI) or troponin T (TnT), are elevated in myocardial necrosis and myocardial infarction. Troponins are also increased in patients with heart failure and myocarditis. Elevated concentration of brain‐type natriuretic peptides (BNP) or N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) is related to myo‐ cardial stretch and left ventricular dysfunction and can be used for screening and prognosis of heart failure (HF) [53, 54]. Suppression of tumorigenicity 2 (ST2), a member of the inter‐ leukin (IL)‐1 receptor family, has two isoforms: transmembrane ST2 and soluble ST2 (sST2). IL‐33 reduces fibrosis and hypertrophy of myocardium, and preserves ventricular function. The sST2 plays a role as a decoy receptor of IL‐33, and binding of IL‐33 and sST2 inhibits the beneficial and protective effect of IL‐33 on the heart. The concentration of sST2 is elevated in patients with HF and is also associated with the prognosis of acute and chronic HF [55].

Many studies reported that NT‐proBNP or BNP was elevated in peripheral blood or UCB with neonates with CHD [56]. A few studies presented the distribution of TnI or TnT in neonates or UCB [57–60]. The distribution and association of sST2 with CHD have not been investi‐ gated yet. There are no current guidelines for their routine use in children. The levels of NT‐ proBNP were significantly increased in UCB of neonates with CHD compared with that in the UCB of control group. In addition, the levels of NT‐proBNP were significantly increased in the neonates with tight ventricular outflow tract obstruction without a ventricular septal defect compared with that in the other groups (**Figure 2**). Moreover, there was significant dif‐ ference between survivors and non‐survivors within one‐year of birth [61]. Hydrops fetalis is fluid collection in multiple body compartments in fetus because of immune or non‐immune mechanism. Congestive heart failure or cardiac dysfunction has been described as one of the major mechanisms for nonimmune hydrops fetalis. The levels of NT‐proBNP in cases with hydrops of cardiac origin were higher than those in cases with hydrops of non‐cardiac origin. However, levels of TnT did not differ though the causes of hydrops fetalis [62].

The only one study reported 97.5th percentile upper reference limit of NT‐proBNP and TnT from healthy neonates, according to the CLSI guideline [21, 63]. In uterus, hemodynamics between pla‐ centa and fetal heart can vary with gestational age [64, 65], and reference intervals for cardiac bio‐ markers in neonates could be different from those in adults. Therefore, establishment of reference intervals is necessary to use cardiac biomarkers in neonates. **Table 3** showed the comparison of sST2, NT‐proBNP, high sensitive TnI, and high sensitive TnT in UCB and adults. For these differ‐ ences between laboratory tests results in UCB and adults, clinical laboratories should establish or verify reference intervals for cardiac biomarkers in UCB. Kim H et al. [66] reported that levels of sST2, NT‐proBNP, and high sensitive TnT in UCB were significantly higher than those in adults.

Reference Intervals of Platelets, Lymphocytes and Cardiac Biomarkers in Umbilical Cord Blood http://dx.doi.org/10.5772/66458 37

**5. Cardiac biomarkers**

36 Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

Congenital heart disease or defect (CHD) is the most common birth defect in newborns [51]. Critical CHDs require intervention or surgery in the first year of life. Echocardiography is a definitive diagnostic tool of CHD and provides hemodynamic and anatomic information of heart. Twenty‐five to 30% of children, however, with critical CHD are not detected by fetal echocardiography until after discharge from the birth hospitalization [52]. Cardiac biomarkers are essential to evaluate heart function and give information of myocardial injury, necrosis, or myocardial stretch. Concentrations of cardiac troponins, troponin I (TnI) or troponin T (TnT), are elevated in myocardial necrosis and myocardial infarction. Troponins are also increased in patients with heart failure and myocarditis. Elevated concentration of brain‐type natriuretic peptides (BNP) or N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) is related to myo‐ cardial stretch and left ventricular dysfunction and can be used for screening and prognosis of heart failure (HF) [53, 54]. Suppression of tumorigenicity 2 (ST2), a member of the inter‐ leukin (IL)‐1 receptor family, has two isoforms: transmembrane ST2 and soluble ST2 (sST2). IL‐33 reduces fibrosis and hypertrophy of myocardium, and preserves ventricular function. The sST2 plays a role as a decoy receptor of IL‐33, and binding of IL‐33 and sST2 inhibits the beneficial and protective effect of IL‐33 on the heart. The concentration of sST2 is elevated in patients with HF and is also associated with the prognosis of acute and chronic HF [55].

Many studies reported that NT‐proBNP or BNP was elevated in peripheral blood or UCB with neonates with CHD [56]. A few studies presented the distribution of TnI or TnT in neonates or UCB [57–60]. The distribution and association of sST2 with CHD have not been investi‐ gated yet. There are no current guidelines for their routine use in children. The levels of NT‐ proBNP were significantly increased in UCB of neonates with CHD compared with that in the UCB of control group. In addition, the levels of NT‐proBNP were significantly increased in the neonates with tight ventricular outflow tract obstruction without a ventricular septal defect compared with that in the other groups (**Figure 2**). Moreover, there was significant dif‐ ference between survivors and non‐survivors within one‐year of birth [61]. Hydrops fetalis is fluid collection in multiple body compartments in fetus because of immune or non‐immune mechanism. Congestive heart failure or cardiac dysfunction has been described as one of the major mechanisms for nonimmune hydrops fetalis. The levels of NT‐proBNP in cases with hydrops of cardiac origin were higher than those in cases with hydrops of non‐cardiac origin.

However, levels of TnT did not differ though the causes of hydrops fetalis [62].

The only one study reported 97.5th percentile upper reference limit of NT‐proBNP and TnT from healthy neonates, according to the CLSI guideline [21, 63]. In uterus, hemodynamics between pla‐ centa and fetal heart can vary with gestational age [64, 65], and reference intervals for cardiac bio‐ markers in neonates could be different from those in adults. Therefore, establishment of reference intervals is necessary to use cardiac biomarkers in neonates. **Table 3** showed the comparison of sST2, NT‐proBNP, high sensitive TnI, and high sensitive TnT in UCB and adults. For these differ‐ ences between laboratory tests results in UCB and adults, clinical laboratories should establish or verify reference intervals for cardiac biomarkers in UCB. Kim H et al. [66] reported that levels of sST2, NT‐proBNP, and high sensitive TnT in UCB were significantly higher than those in adults.

**Figure 2.** The distribution of NT‐proBNP levels in the umbilical cord blood of neonates with cardiac malformations according to the type. Abbreviations: HLHS, hypoplastic left heart syndrome; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; RVOTO, right ventricular outflow tract obstruction; TOF, tetralogy of Fallot. Adapted from [61] with permission of Springer International Publishing AG.


sST2, soluble suppression of tumorigenicity 2; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; hs‐TnI, high sensitive troponin I; hs‐TnT, high sensitive troponin T; UCB, umbilical cord blood.

**Table 3.** Comparison of sST2, NT‐proBNP, high sensitive TnI, and high sensitive TnT in UCB and adults. Adapted from [66] with permission of Walter de Gruyter GmbH.
