Andersons pediatric cardiology 158

Biophysical Properties of Fetal Myocardium The biophysical characteristics of fetal, neonatal, and adult myocardium have been investigated in a number of mammalian species, but studies in the sheep and rabbit have provided the majority of information11,12 (see also Chapter 4) These studies have consistently demonstrated that active development of tension is lower in fetal than adult myocardium at all lengths, including the optimal length.11 In addition, in the ovine fetus, resting tension is greater than that in the adult animal The difference in developed tension cannot be accounted for entirely by the greater proportion of noncontractile protein per unit cross-sectional area of fetal myocardium It may be explained in part by the different sensitivity of the fetal contractile proteins troponin and myosin to cytosolic calcium.12 In the early human fetus, handling of calcium depends on diffusional gradients through the sarcolemma in the absence of a developed sarcoplasmic reticulum Sarcoplasmic calcium adenosine triphosphatase (ATPase) is expressed in a downstream gradient along the primitive heart tube, resulting in increased contraction duration in the outlet portions of the heart By the 38th day of gestation, the early human myocardium may be divided into primary and working functional components The primary components are characterized by slow conduction of the cardiac impulse, owing to the low density of gap junctions and the presence of slow voltage-gated calcium ion channels The working components, found in the atriums and ventricles, permit fast conduction through the development of gap junctions and of fast voltage-gated sodium channels The sarcoplasmic reticulum later regulates calcium release in the cell and is known to play an important role in the frequency-dependent facilitation of the L-type calcium current in the rat ventricular myocyte.13 The three major connexins, 40, 43, and 45, are present in cardiac myocytes and are developmentally regulated Immunoconofocal microscopy has been used to compare the distribution of these within the developing mouse and human heart In the human, connexin 45 is most prominent in the conduction tissues, connexin 40 is also abundant in conduction tissues, particularly in the Purkinje fibers and in the atrial rather than in the ventricular muscle, whereas connexin 43 is distributed in the ventricular myocardium and plays an important role in conduction across gap junctions.14 Knock-out mice models have increased our understanding of the pathophysiologic role of connexin diversity in the heart.15 This may permit the development of connexin-specific treatment strategies to treat heritable arrhythmias affecting the fetus Chronic exposure to an adverse intrauterine environment, such as chronic hypoxemia associated with restriction of growth, or in conditions with abnormal volume loading may result in altered patterns of calcium ionic fluxes and of abnormal β-adrenoceptor stimulation similar to that identified in diseased adult myocardium.16 Protein Components Troponin The differences between fetal and adult myocardial contractile function are, in large part, related to their regulatory and structural protein components Different isoforms of troponin and myosin heavy chain have been identified in fetal and adult myocardium from a number of mammalian species, including humans These are genetically programmed during early embryonic development and are modulated by specific neurohormones, including thyroid hormone Troponin T has been studied extensively and cloned It regulates contraction in response to the concentration of ionic calcium.17 Multiple isoforms have been recognized, the gene TNNT2 being identified on chromosome 1q23 Slow skeletal muscle troponin T is the predominant isoform throughout fetal life, and its switch to the cardiac form appears to define myofilament calcium sensitivity.18 In the human, this transition occurs between 20 and 33 gestational weeks,19 with only the cardiac isoform of troponin I detectable by 9 months of postnatal life.20 The genes coding for these two isoforms lie in close apposition but show independent tissue-specific expression, although this close arrangement may complicate investigation of mutations implicated in cardiomyopathy.21 A knock-out model of myocardial troponin I showed that, although affected mice are born healthy, they begin to develop heart failure by 15 days They have an isoform of troponin I that is identical to slow skeletal troponin I, permitting survival, but this isoform disappears after birth despite the lack of compensatory myocardial troponin I Consequently, the ventricular myocytes have shortened sarcomeres and elevated resting tension, and they show reduced sensitivity of their myofilaments to calcium under activating conditions.22 β-Myosin The β-myosin heavy chain isoform predominates in all fetal mammals thus far examined, including humans This isoform is advantageous in the fetus because it uses less oxygen and ATP than the adult α-isoform to generate the same amount of force Recent investigations have shown repression of fetal genes that downregulate adult, but not fetal, isoforms in response to increased cardiac work and subsequent mechanical unloading This response appears to result in