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In order to study the changes in the pattern of autonomic innervation of the human cardiac conduction system in relation to age, the innervation of the conduction system of 24 human hearts (the age of the individuals ranged from newborn to 80 years), freshly obtained at autopsy, was evaluated by a combination of immunofluorescence and histochemical techniques. The pattern of distribution and density of nerves exhibiting immunoreactivity against protein gene product 9.5 (PGP), a general neural marker, dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH), indicators for presumptive sympathetic neural tissue, and those demonstrating positive acetylcholinesterase (AChE) activity, were studied. All these nerves showed a similar pattern of distribution and developmental changes. The density of innervation, assessed semiquantitatively, was highest in the sinus node, and exhibited a decreasing gradient through the atrioventricular node, penetrating and branching bundle, to the bundle branches. Other than a paucity of those showing AChE activity, nerves were present in substantial quantities in infancy. They then increased in density to a maximum in childhood, at which time the adult pattern was achieved and then gradually decreased in density in the elders to a level similar to or slightly less than that in infancy. In contrast, only scattered AChE-positive nerves were found in the sinus and atrioventricular nodes, but were absent from the bundle branches of the infant heart, whereas these conduction tissues themselves possessing a substantial amount of pseudocholinesterase. During maturation into adulthood, however, the conduction tissues gradually lost their content of pseudocholinesterase but acquired a rich supply of AChE-positive nerves, comparable in density to those of DBH and TH nerves. The decline in density of AChE-positive nerves in the conduction tissues in the elders was also similar to those of DBH and TH nerves. Our findings of initial sympathetic dominance in the neural supply to the human cardiac conduction system in infancy, and its gradual transition into a sympathetic and parasympathetic codominance in adulthood, correlate well with the physiologic alterations known to occur in cardiac rate during postnatal development. The finding of reduction in density of innervation of the conduction tissue with ageing is also in agreement with clinical and electrophysiological findings such as age-associated reduction in cardiac response to parasympathetic stimulation. Finally, our findings also support the hypothesis that, in addition to the para-arterial route, the parafascicular route of extension along the conduction tissue constitutes another pathway for the innervation of the conduction system of the human heart during development. Anat Rec 264:169–182, 2001. © 2001 Wiley-Liss, Inc.
The cardiac conduction system, consisting of the sinus node, the specialised atrioventricular junctional area and the ventricular conduction tissues, is responsible for the generation and coordination of transmission of electric impulse in the heart, resulting in its rhythmic and synchronized contraction. The morphology of the cardiac conduction system itself has been studied in detail in many animal species (Anderson, 1972a,b; Bleeker et al., 1980; Roberts et al., 1989; Forsgren et al., 1983; Op'thof et al., 1987), including the human being (Anderson et al., 1975; Smith et al., 1977; Davies et al., 1983a).
Interest in the analysis of cardiac innervation has recently been stimulated by the availability of sensitive immunohistochemical techniques, which have allowed better visualization and determination of the pattern of distribution of the various nerve subtypes (Weihe et al., 1984; Sternini and Brecha, 1985; Dalsgaard et al., 1986). Indeed, such techniques have been applied to the detailed analysis of cardiac innervation, including that of the conduction system, of several mammalian species (Roberts et al., 1989; Ursell et al., 1990, 1991a, 1991b; Choate et al., 1993; Slavikova et al., 1993; Zhang et al., 1993; Crick et al., 1996). Similar studies have also been performed on the human heart (Rechardt et al., 1986; Wharton et al., 1988, 1990; Chow et al., 1993, 1995; Gordon et al., 1993; Crick et al., 1994; Marron et al., 1994, 1995), but those with emphasis on the conduction system have been few (Chow et al., 1993; Crick et al., 1994). Moreover, while the innervation of the neonatal and adult human cardiac conduction system have been analyzed (Chow et al. 1993; Crick et al. 1994), information concerning its postnatal maturation during infancy and childhood, and the changes occurring during adolescence, adulthood and senility, is lacking.
On the other hand, it is well known that the cardiac rate of newborn infants is rapid, and subject to wide fluctuations (Behrman et al., 1992). The average rate ranges from 120 to 140 beats per minute, and may increase to 170 or more during crying and activity, or drop to 70–90 during sleep. As the child grows older, the average cardiac rate becomes slower, as low as 40 per minute in athletic adolescents. This variation may well be related in part to the functional development of the cardiac conduction system, and it is not unreasonable to speculate that changes in the pattern of innervation of the conduction tissues, for which detailed analysis has not been performed, may be one of the anatomical changes contributing to such an alteration.
In addition, several groups of investigators, using experimental animal models and by virtue of clinical observations, have provided evidence linking the autonomic nervous system and sudden cardiac death (Corr et al., 1986; Schwartz and Stramba-Badiale, 1988; Schwartz and Priori, 1990). For example, there is now general consensus that in the setting of acute myocardial ischaemia, sympathetic hyperactivity facilitates the onset of malignant arrhythmias, whereas vagal activation can exert an antifibrillatory effect, and these findings have been used in the identification of individuals at high risk of, and in the development of therapeutic strategies for the prevention of sudden cardiac death (Schwartz et al., 1994). In this respect, it is of interest to note that abnormalities of the cardiac conduction system have also been suggested to be the underlying cause for cases of sudden infant death syndrome (Davies et al., 1983b). Even though the issue remains controversial, detailed analysis of the autonomic innervation of the heart (notably that of the conduction system) in cases of sudden infant death syndrome, which has not yet been performed, would be of value.
Furthermore, while the anatomic basis of certain types of conduction defects, such as isolated congenitally complete heart block, is well described (Chow et al., 1998a), no consistent structural abnormality is found in others, as exemplified by the conduction defects associated with various types of neurological and myopathic syndromes (Davies et al., 1983c). In Duchenne muscular dystrophy, for example, the pathological changes of the heart, consisting of dilatation, hypertrophy, and fibrosis of both atria and ventricles, are fairly nonspecific. While it has been suggested that selective fibrosis in the posterobasal region of the left ventricle was responsible for the electrocardiographic changes characteristic of this condition (Davies et al., 1983c), this finding is by no means universal and other concomitant abnormality, notably that of the conduction system, may also contribute to the pathogenesis of the conduction defect. In this latter group of conduction disorders, it would be of interest to analyse the innervation of the conduction system, especially in light of the recent evidence of the dominant role of the autonomic nervous system in the genesis and modulation of cardiac arrthymias (Corr et al., 1986; Schwartz and Stramba-Badiale, 1988; Schwartz and Priori, 1990; Schwartz et al., 1994). In this regard, the importance of defining the normal pattern of innervation of the conduction system in various age groups cannot be overemphasized.
In the present study, therefore, we attempted to fill the gap in our knowledge by studying the changes in the pattern of innervation of the human cardiac conduction system from infancy to senility, employing a combination of immunohistochemical and histochemical techniques.
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In summary, our present study has shown that PGP, DBH, TH, and AChE innervation of the conduction system of the human heart show a similar pattern of distribution and developmental changes. The density of innervation is highest in the sinus node, and exhibits a decreasing gradient through the atrioventricular node, penetrating and branching bundles, to the bundle branches. Apart from AChE-positive nerves, the other types are already present in substantial quantities in infancy, but do increase in density in childhood, when the adult pattern is achieved. In contrast, only scattered AChE-positive nerves are found in the sinus and atrioventricular nodes, but not in the bundle branches of the infant heart, whereas these conduction tissues themselves possess a significant amount of pseudocholinesterase. With maturation into adulthood, however, the conduction tissues gradually lose their cholinesterase content but acquire a rich supply of AChE-positive nerves, comparable in density to those of DBH and TH nerves.
Our findings of initial sympathetic dominance in the neural supply of the human cardiac conduction system in infancy, and its gradual transition into a sympathetic and parasympathetic codominance in adulthood, correlate well with, and may constitute one of the anatomical bases for the physiologic alterations in cardiac rate known to occur during development. The findings are important clinically because they show that, in addition to marked differences in innervation of the conduction tissues among species, equally important changes occur with development in the pattern of innervation in the same species, namely, human.