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Technical Briefs |
1
1st Lab. of Clin. Chem. and
2
Neonatal Intensive Care Unit, Spedali Civili, and
3
Div. of Cardiol., Umberto I Hosp., 25125 Brescia, Italy;
a author for correspondence: fax 39-30-3995430
In neonates, acute perinatal asphyxia may lead to ischemic myocardial damage (1). In some cases, subendocardial infarction has been documented (2). Generally, diagnosis of the myocardial injury (MI) is based on clinical findings, suggestive electrocardiographic and echocardiographic patterns (3), decrease in myocardial uptake of thallium (4), and classical creatine kinase (CK)-MB isoenzyme measurement (5). However, CK-MB in serum cannot be regarded as a cardiac-specific marker in the neonate, and extreme caution should be used in the interpretation of increased CK-MB activity during this period (6). Cardiac troponin T (cTnT), the structural protein that binds the troponin complex to the tropomyosin molecular strand, has recently been proposed as a more specific biochemical marker for diagnosis of myocardial infarction in the adult population (7). Here we evaluated the use of cTnT measurement in serum in the diagnosis of MI in newborns, as well as that of the determination of CK-MB mass concentration by a sensitive and specific monoclonal anti-CK-MB antibody-based immunoassay.
Three groups of infants were studied. Group I consisted of 27 preterm
infants (gestational age ranging from 28 to 36 weeks) without major
respiratory and cardiovascular dysfunctions. Group II was 27 healthy
full-term newborns (15 born by vaginal delivery and 12 by cesarean
section) with a mean gestational age of 39.7 weeks. Group III was
composed of seven infants (four preterm and three term) who
demonstrated, during the first 3 days after birth, clinical,
electrocardiographic, and echocardiographic signs of MI. In particular,
in electrocardiogram (ECG) evaluation, MI was considered to be present
when inversion of T waves or ST-segment depression 
1 mm in more than
two precordial leads was noted. Groups I and II underwent a clinical
examination, ECG, echocardiogram, and blood collection for the
measurement of total CK, CK-MB, and cTnT on day 2 after birth. Group
III was evaluated with ECG and echocardiography at presentation and
every 24 h until clinical recovery or death. Total CK, CK-MB, and
cTnT were measured 12 and 48 h after presentation and, when
possible, after 45 days. The protocol of the study was approved by the
local Ethical Committee, and parental consent was obtained.
An ELISA (Boehringer Mannheim, Mannheim, Germany) was used to determine cTnT in serum (detection limit, 0.02 µg/L). Total CK activity was measured at 37 °C by the method recommended by the IFCC. CK-MB mass concentrations were determined with the Magic Lite CK-MB assay (Ciba Corning Diagnostic Corp., Medfield, MA). A relative index (RI), i.e., (CK-MB, µg/L/total CK, U/L) x 100, was also calculated. In adults, the upper reference limit (URL) is 0.10 µg/L for cTnT, 175 U/L for total CK, 6.0 µg/L for CK-MB, and 3% for RI.
M-mode, two-dimensional, and pulsed Doppler echocardiographic examinations were performed with an Acuson echocardiograph (Acuson, Mountain View, CA) with a 7.5-MHz transducer. Each patient was examined according to the standards of the American Society of Echocardiography (8), and echocardiograms from MI infants were compared with those of infants without MI of similar gestational age. Left ventricular fractional shortening was calculated by the following formula: [left ventricular-end diastolic diameter (LVDD) - left ventricular-end systolic diameter x 100]/LVDD. Cardiac output was measured by multiplying the aortic flow integral by the area of the aortic orifice. Mitral and tricuspid incompetence were graded as trivial, mild, moderate, and severe.
In group I, four infants were small for gestational age, but none had positive cardiovascular examination and ECG. At echocardiography, LVDD (12.6 ± 1.6 mm) was within the previously reported age-related limits (9) and was positively related to weight (r = 0.71, P <0.001) and gestational age (r = 0.65, P <0.001). Fractional shortening (40.8% ± 7.2%) and cardiac output (0.81 ± 0.32 L/min) were also within normal limits, and no signs of pulmonary hypertension were pointed out (mean right ventricular pressure ± SD, 23.9 ± 9.4 mmHg). Trivial mitral incompetence was present in two infants, both born at 28 weeks' gestation. The incidence of tricuspid incompetence (no more than mild), present in 20 infants, decreased with increase in gestational age.
All healthy full-term newborns (group II) also had negative clinical examination results and normal ECGs and echocardiograms. Furthermore, the method of delivery did not affect the concentrations of biochemical markers studied. Total CK and CK-MB concentrations were significantly (P <0.001) lower in group I than in group II (mean CK ± SE, 246 ± 57 U/L vs 751 ± 102 U/L; mean CK-MB ± SE, 9.8 ± 1.5 µg/L vs 29.1 ± 3.5 µg/L, respectively), even if RI did not change between the two groups (5.1% ± 0.5% vs 4.3% ± 0.3%, P = 0.34), suggesting that the difference in enzyme concentration reflected a difference in skeletal muscle mass. Indeed, total CK and CK-MB values were significantly correlated to birth weight (r = 0.50, P <0.001 for total CK, and r = 0.56, P <0.001 for CK-MB) and to gestational age (r = 0.56, P <0.001 for total CK, and r = 0.60, P <0.001 for CK-MB).
cTnT did not change with gestational age (r = 0.20, P = 0.15), and no correlation was found between values for serum cTnT and total CK activity (r = 0.24, P = 0.08) or between cTnT and CK-MB mass concentration (r = 0.21, P = 0.12). However, virtually all healthy children (group I and II) had detectable cTnT (mean, 0.16 µg/L; range, 0.04–0.43 µg/L).
The 95th percentile values for these biochemical markers in healthy newborns were: total CK (preterm), 635 U/L; total CK (term), 2126 U/L; CK-MB (preterm), 26 µg/L; CK-MB (term), 72 µg/L; RI, 8.8%; cTnT, 0.33 µg/L.
Clinical, echocardiographic, electrocardiographic, and biochemical
findings of the newborns with MI are shown in Table 1
. Evidence of MI occurred at 2.1 ± 0.7 days. Five infants
(infants 1, 2, 4, 5, and 6) had signs of congestive heart failure and
two (infants 1 and 2) suffered from cardiogenic shock. Infant 5 had
bradyarrhythmias (sinus bradycardia and atrioventricular block with
complete right bundle branch block) refractory to atropine and
isoproterenol treatment. Patient 1 died on day 4 in consequence of
cardiogenic shock. Patient 5 had cardiac arrest on day 2 with
unsuccessful cardiac resuscitation; autopsy revealed a pale myocardium,
with histologic signs compatible with recent hypoxic damage. Five
babies survived. In these subjects, clinical recovery occurred 3–9
days after birth. All had complete normalization of contraction, left
ventricular fractional shortening (from 26.0% ± 5.8% at admission to
41.6% ± 2.4% after 45 days), and cardiac output (from 0.63 ±
0.36 L/min at admission to 1.40 ± 0.33 L/min after 45 days).
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None of the MI patients had increased CK-MB mass concentration in serum. One infant (infant 6) had a slight increase in total CK but normal CK-MB concentration, suggesting that the increase in CK activity was a result of MM isoenzyme, presumably released from skeletal muscle. By contrast, all infants with congestive heart failure had increased cTnT. In particular, four patients had extremely high values for cTnT (>0.70 µg/L), including the two babies who died. In the two babies of this subgroup who survived, cTnT measured after 45 days was within the reference range of adults.
Our findings demonstrated that serum of apparently healthy infants has a high concentration of CK-MB protein when compared with adult reference limits, the highest values being found in term infants. Therefore, the adult URL for CK-MB is not useful for infants; furthermore, the relationship between enzyme concentration and gestational age suggests also that this finding should be considered when interpreting concentrations of this marker after birth. The reason is probably the known increased synthesis of the B subunit in skeletal muscle of the fetus (10). This could also account for the increase of RI values over the adult URL and for the constant proportion that the CK-MB fraction represents of the total CK in term and preterm infants. In view of the high and scattered concentrations of CK-MB released from the skeletal muscle in serum of healthy neonates, this biochemical marker was unable to identify the cardiac damage in the neonates with MI, even with a highly sensitive and specific last-generation immunoassay.
Unlike the considered enzymes, the concentration of cTnT in serum on day 2 after birth was independent of gestational age, although the URL was substantially higher than in adults or older children (11). cTnT is increased also in newborn animals (12). The reported concentrations of cTnT could have been affected by crossreactivity with skeletal troponin T in the first-generation cTnT assay that was used (13). The lack of substantial correlation between CK, CK-MB, or gestational age and cTnT do not support this possibility. Anderson et al. (14) found small amounts of cTnT isoforms in skeletal muscle obtained from aborted fetuses after 14–15 weeks of gestation, and Mesnard et al. (15) showed that cTnT is indeed coexpressed in fetal skeletal muscle, its expression being down-regulated during further development. These developmental changes in troponin T gene regulation could partially explain the increased cTnT in the early neonatal period.
Although the number of patients was relatively small, our study raises the possibility that the serum concentration of cTnT might be of diagnostic value in young children with suspected myocardial damage. As recently discussed (16), great caution is, however, necessary before one can derive definitive conclusions on the value of new biochemical markers in this particular clinical setting.
Acknowledgments
We thank Francesca Stefini and Cristina Serena for technical assistance. We are also indebted to the nursing staff of the Neonatal Intensive Care Unit for the assistance in the collection of the blood samples.
References
The following articles in journals at HighWire Press have cited this article:
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  W B Borke, B H Munkeby, L Morkrid, E Thaulow, and O D Saugstad Resuscitation with 100% O2 does not protect the myocardium in hypoxic newborn piglets Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2004; 89(2): F156 - F160. [Abstract] [Full Text] [PDF]
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 H. H. Hovels-Gurich, J. F. Vazquez-Jimenez, A. Silvestri, K. Schumacher, R. Minkenberg, J. Duchateau, B. J. Messmer, G. von Bernuth, and M.-C. Seghaye Production of proinflammatory cytokines and myocardial dysfunction after arterial switch operation in neonates with transposition of the great arteries J. Thorac. Cardiovasc. Surg., October 1, 2002; 124(4): 811 - 820. [Abstract] [Full Text] [PDF]
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