Cardiac Maturation

Although the embryonic heart is fully formed and functional by the 11th week of pregnancy, the fetal and neonatal heart continue to grow and mature rapidly, with many clinically relevant changes taking place after birth. During fetal development, or from the time after the embryo is completely formed in the first trimester of pregnancy until birth, the heart grows primarily by the process of cell division (28-31). Within a few weeks after birth, the predominant mechanism of cardiac growth is cell hypertrophy; in other words, existing cardiac cells become larger rather than increasing significantly in number (28-30).

The exact timing of this process and the mechanisms regulating these changes are not yet completely elucidated. In the classic explanation, mature cardiac cells lose the ability to divide; however, more recent work suggests that a limited amount of cell division can occur in adult human hearts damaged by ischemia (32). This finding has led to a renewed interest in understanding the regulation of cell division during cardiac maturation. Additional maturational changes in both the fetal and neonatal heart include alterations in the composition of cardiac muscle, differences in energy production, and maturation of the contractile function. These changes, along with associated physiological changes in the transitional circulation, as discussed in Section 4, affect the treatments of newborns with congenital heart disease, particularly those requiring interventional procedures or cardiac surgery.

The hemodynamic changes associated with birth include a significant increase in left ventricular cardiac output to meet the increased metabolic needs of the newborn infant. This improvement in cardiac output occurs despite the fact that the neonatal myocardium has less muscle mass and less cellular organization than the mature myocardium. The newborn myocardium consists of 30% contractile proteins and 70% noncontractile mass (membranes, connective tissues, and organelles), in contrast to the adult myocardium, which is 60% contractile mass (30). The myocardial cells of the fetus are rounded, and both the myocardial cells and myofibrils within them are oriented randomly. As the fetal heart matures, these myofibrils increase in size and number and orient to the long axis of the cell, which further contributes to improved myocardial function (28). The fetal myocardial cell contains higher amounts of glycogen than the mature myocardium, suggesting a higher dependence on glucose for energy production; in experiments in nonprimate model systems, the fetal myocardium is able to meet its metabolic needs with lactate and glucose as the only fuels (33). In contrast, the preferred substrate for energy metabolism in the adult heart is long-chain fatty acids, although the adult heart is able to utilize carbohydrates as well (33,34). This change is considered to be triggered in the first few days or weeks of life by an increase in serum long-chain fatty acids with feeding, but the timing and clinical impact of this transition relative to an ill or nonfeeding neonate with cardiovascular disease is currently unknown.

In addition, the maturing myocardial cells undergo changes in the expression of their contractile proteins, which may be responsible for some of the maturational differences in cardiovascular function. Changes in expression of contractile proteins that may be important in humans include a gradual increase in the expression of myosin light chain 2 (MLC 2) in the ventricle from the neonatal period through adolescence. In the fetal ventricle, two forms of myosin light chain, MLC 1 and MLC 2, are expressed in equal amounts (30,35). Increased MLC 1 expression is associated with increased contractility; for example, it has been documented in isolated muscle from patients with tetralogy of Fallot that both MLC 1 expression and contractility are increased (36). After birth, there is a gradual increase in the amount of MLC 2, or the "regulatory" myosin light chain, which has a slower rate of force development but can be phosphorylated to increase calcium-dependent force development in mature cardiac muscle (30,37).

There is also variability in actin isoform expression during cardiac development. The human fetal heart predominantly expresses cardiac a-actin; the more mature human heart expresses skeletal a-actin (28,38). Actin is responsible for interacting with myosin cross bridges and regulating adenos-ine triphosphatase (ATPase) activity, and work done in the mouse model system suggests that the change to skeletal actin may be an additional mechanism of enhanced contractility in the mature heart (28,39,40).

There are also developmental changes of potential functional significance within the regulatory proteins of the sarcomere. More specifically, the fetal heart expresses both a- and p-tro-pomyosin, a regulatory filament, in nearly equal amounts; after birth, the proportion of p-tropomyosin decreases, and a-tro-pomyosin increases, potentially to optimize diastolic relaxation (28,41,42). Interestingly, an expression of high levels of p-tro-pomyosin in the neonatal heart has been linked to early death caused by myocardial dysfunction (43).

Last, the isoform of the inhibitory troponin, troponin I, also changes after birth. The fetal myocardium contains mostly the skeletal isoform of troponin I (28,44); after birth, the myocardium begins to express cardiac troponin I, and by approx 9 mo of age, only cardiac troponin I is present (28,45,46). It should also be noted that cardiac troponin I can be phosphorylated to improve calcium responsivity and contractility, which may improve function in the more mature heart; it is thought that the skeletal form of troponin I may serve to protect the fetal and neonatal myocardium from acidosis (30,39,47).

In summary, the full impact of these developmental changes in contractile proteins and their effect on cardiac function or perioperative treatment of the newborn with heart disease remains unclear at the present time. However, such insights may provide future modes for optimizing therapy in children.

Two of the most clinically relevant features of the immature myocardium are its requirement for high levels of extracellular calcium and a decreased sensitivity to p-adrenergic inotropic agents. The neonatal heart has a decrease in both volume and functional maturity of the sarcoplasmic reticulum, which stores intracellular calcium (28). The paucity of intracellular calcium storage and subsequent release via the sarcoplasmic reticulum in the fetal and neonatal myocardium increases the requirements of these myocardia for extracellular calcium, so that exogenous administration of calcium can be used to augment cardiac contractility in the appropriate clinical setting. In addition, neonates and infants are significantly more sensitive to calcium channel blocking drugs than older children and adults and thus are at a higher risk for severe depression of myocardial contractility with the administration of these agents (28,30,48).

Last, although data in humans are limited, there appears to be significantly decreased sensitivity to p-agonist agents in the immature myocardium and in older children with congenital heart disease (30,49-51). This may be attributable to a paucity of receptors, sensitization to endogenous catechola-mines at birth or with heart failure, or a combination of these and/or additional factors. Because of this decreased responsiveness to p-agonists, there is a common requirement clinically for administrating higher doses of p-agonist inotropic agents in newborns and infants. Importantly, alternative medications, including phosphodiesterase inhibitors, are often useful adjuncts to improve contractility in newborns with myocardial dysfunction (30).

Although the structure of the heart is complete in the first trimester of pregnancy, cardiac growth and maturation occur in the fetus, newborn, and child. Many of these developmental changes, particularly decreased intracellular calcium stores in the immature sarcoplasmic reticulum and a decreased responsiveness to p-agonist inotropic agents, have a significant impact on the care of newborns, infants, and children with congenital heart disease, particularly those requiring surgical intervention early in life.

Pregnancy Diet Plan

Pregnancy Diet Plan

The first trimester is very important for the mother and the baby. For most women it is common to find out about their pregnancy after they have missed their menstrual cycle. Since, not all women note their menstrual cycle and dates of intercourse, it may cause slight confusion about the exact date of conception. That is why most women find out that they are pregnant only after one month of pregnancy.

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