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This paper presents an overview of cardiac chronotropic regulation determinants in newborns, which are reflected in mean heart rate (HR) and heart rate variability (HRV). Heart rate and heart rate variability in newborns are determined by many factors. Heritability and maturation play major role. Factor of the maturation can be seen in HR and HRV differences between healthy full term and preterm newborns as well as in changes over early postnatal time. These parameters in newborns are influenced also by many other factors as gender, nutrition, sleep, breathing pattern/ventilation, etc. Autoregulation and extrinsic regulation of cardiactivity has its own specificities in newborns. Homeometric mechanism (depended on HR) is dominannd baroreflex sensitivity is reduced, mainly in premature newborns. Complex cardiac regulation can be studied and evaluated by cardiac reflexes. Examination of the reflexes in newborns is limited. Therefore, new approaches for the study of maturation cardiac control are developed taking into consideration all cardiactivity in newborns determinants. Keywords: newborn, prematurity, heart rate, heart rate variability, regulation of cardiac function, autonomic nervous system, cardiac reflexes INTRODUCTION Newborns for rapid transition from fetal to postnatal life must have properly developed functioning systems including their intrinsind extrinsic (nervous and humoral) control mechanisms. Everything, even linically asymptomatic dysregulation can be followed by a maladaptation with potential serious consequences, that can occur later. Therefore, the research in physiology and neonatology deals with the determinants of cardiactivity, cardiovascular system (CVS) control mechanisms, dysregulation, relationships to neonatal morbidity, mortality, and with searching for and developing new methods for early diagnosis of the cardiovascular dysregulation. DETERMINANTS OF CARDIAC CHRONOTROPIC CONTROL Heritability Heritability determines many vital characteristics including heart rate (HR) and heart rate variability (HRV) through determination of developmennd functions all structures and molecules involved in cardiactivity control, including receptors, neurotransmitters, autonomic nervous system, etc. Therefore, the heritability can play major role in determination of cardiac chronotropic characteristics. Singh and co-workers (1) assessed the impact of heritability and environment (household effects) on HR and HRV in a large number of families. Heritability analysis was done by studying correlations between siblings and spouse pairs. After adjusting for Address for correspondence: Kamil Javorka, Prof., MD., DSc. Department of Physiology, Jessenius Faculty of Medicine, Comenius University, Mala Hora N.4, 036 01 Martin, Slovakia. e-mail: firstname.lastname@example.org covariates, the correlations were consistently higher among siblings (0.21 0.26) compared with spouses (0.01 0.19). The measured covariates in general accounted for 13% to 40% of the total phenotypic variance, whereas genetic factors accounted for 13% to 23% of the variation among HR and HRV measures. Even greater genetic determination of RR intervals was found by other authors. Kupper el. (2) studied 780 healthy twins and siblings. RR intervals and thus the heart rate (HR) were genetically determined from 37 to 48%, respiratory sinus arrhythmia (RSA) from 40% - 55%. The importance of genetic factors to the HRV significantly increases at resnd during night, the covariance between respiration rate and RSA in these conditions was completely determined by common genes. Using univariate and multivariate statistical analysis, Uusitalo el. (3) found that genetic factors accounted for a major portion (31 57%) of the interindividual differences in HRV. The influence of genotype on HR and HRV is highly complex due to complexity of cardiovascular regulation. This is why the exact genes determining HRV are not definitively known. Martin el. (4) who estimated the heritability of resting heart rate to be 26 ± 5% in healthy subjects, obtained evidence of linkage for the HR on chromosome 4. This signal is in the same region as a quantitative trait locus (QTL) for long QT syndrome. There are two strong candidate genes: ankyrin-B (ANKB) and myozenin 2 (MYOZ2). Ankyrin promotes targeting of ion channels to the proper membranes in cells, myozenin 2 may indirectly (through calcineurin activation) influence calcium signalling and pacemaker function. Other authors (5) identified in mice a significant quantitative trait locus (QTL) for HR on chromosome 6, QTL for total power (TP) HRV on chromosomes 2, 4, 5, 6, 14, for low frequency band (LF) on chromosome 16 and for high frequency band activity on chromosome 5, 2,11 and 15. Attention was focused on the gene for neurotransmitter acetylcholine, for the choline transporter gene, as well as the adrenergic receptors (6) and the D5 dopamine receptor (5). Recently the list of candidate genes for determination chronotropic cardiac regulation is not definitive. But it is clear, that heritability plays an important role in determination of cardiac regulation in healthy humans and may explain a substantial proportion of the interindividual variance in HR and HRV. ,,Tracking phenomenon" DiPietro el. (7) found that the dynamic parameters of fetal circulation, and some maternal physiological parameters (blood pressure, blood oxygen saturation) correspond to the 40-48% for the characteristics of heart rate (HR) and heart rate variability (HRV) in newborns and infants up to the end of the first year of life. Increased fetal heart rate is reflected in a higher mean heart rate in the newborns. Significant intraindividual stability of heart rate nad HRV were found not only during the prenatal period (fetal HR and HRV were measured and evaluated longitudinally from 20 through 38 weeks of gestation) but up to the postnatal age two (9). Even a small but significant relation has been shown between prenatal and postnatal heart rate age ten (8). It indicates some ,,stability" (inertia) of the cardiovascular parameters characteristics - tracking phenomenon - which transmits some characteristics from prenatal to postnatal life, of course, also on the base of the genetic determinants. In the following paper, DiPietro el. (8) investigated also whether fetal HR and HRV are useful predictors of child developmental outcome. They hypothesized that slower HR and higher level of variability would be reflected in more advanced development of functions in early childhood. They found that fetuses with slower and more variable heart rates (greater HRV) had latter - age 2 years - significantly higher Mental and Psychomotor Development Index (MDI, PDI) and better language development than those with faster and more fixed heart rates. Similar results associations between vagal tone and neonatal attentional orientation have been shown by Feldman (10), between HRV and MDI scores at 1 year by Richards (11), and between respiratory sinus arrhythmia and standardized cognitive test scores in middle childhood by El-Sheikh and Buckhalt (12). All these data suggest that magnitude and development (trajectories) of fetal heart rate variability during prenatal life correspond (to ertain level) with maturation of CNS including of autonomic nervous system and with mental and psychomotor development of individuals. It seems that features of the fetal HRV, and due to the tracking phenomenon also neonatal HRV, may provide chance to indirectly assess the nervous system development. Age Studies about the relationship between HR, HRV and gestational, respectively postnatal or postconceptional age have shown that the lower are these ages, the higher is mean heart rate and the more reduced is HRV. It is very likely that these findings relate to the maturity of individual components of the chronotropic controller incl. the autonomic nervous system (13). Therefore, when interpreting the results of HRV analysis in newborns, it must be taken into account this age determinannd results should be evaluated regarding appropriate values for each (gestational/postconceptional) age group. For newborns, reference values of longterm HRV were published by Mehta el. (14), values obtained by spectral analysis of shortterm HRV are in papers of Kantor and Javorka (15), Lehotska el. (16) and Yang el. (17). Gestational age prematurity: Premature newborns have regulations of functions programmed primarely for appropriate development in the intrauterine environmennd thus they are not completely adapted to the physiological demands of extrauterine life (18). Premature infants have a reduced HRV even withouny sign of maladaptation to extrauterine life. Aarimaa and Oja (19) found in full term healthy newborns that in HRV was initially present the peak spectral activity in the low-frequency (LF) band (with sympathetic component) and later, at 5th postnatal day, appeared peak spectral activity also in the HF (parasympathetic) band. In healthy preterm infants was present in the 5th postnatal day just LF peak, with no significanctivity in the HF band even during quiet NREM sleep. This deficit is possibly associated with the immaturity of the autonomic nervous system. Maturation of CNS/ANS is then accompanied by an increase HRV due to enhancement of parasympathetic (HF) activity (20,21,22). As can be seen, the biggest difference in HRV between the premature and full term newborns is reduced or completely absenctivity in HF parasympathetic band. Postnatal age: The development of autonomic innervation of the heart, which affects the heart rate and HRV is not yet completed after birth. Parasympathetic tone is weak, and this is reflected in a higher resting mean heart rate. In results of HRV spectral analysis is typical dominance of activity in low-frequency band with sympathetic component. Some role can play also postnatal stress. Although transfer of results from animal experiments to human physiology must be done very carefully, experiments on newborn lambs showed that only on the third postnatal month is developed noticeable effect of the parasympathetic regulation on cardiac function (23). However, in human newborns even in the first postnatal days were elicitable cardiac inhibitory reflexes, for example oculocardiand Cushing`s reflex (24; Fig.1). These reflexes resulting in bradycardia may have a physiological role in rapid adaptation of coronary perfusion and heart metabolism at normal vaginal delivery when the fetal head is squeezed and retroorbital and intracranial pressures are increased. Fig. 1 Changes in instantaneous beat-to-beat heart rate (HR) and respiratory movements (Resp.) in premature newborn elicited by stimulation pressure applied on large fontanelle. Cushing reflex-like bradycardic reaction. During the first postnatal days, the development of body systems including their control mechanisms is accelerated. HRV parameters significantly increase in all bands reflecting sympathetind parasympathetic regulation in the first three postnatal days (25). The rapid development of HRV in full term healthy newborns was confirmed by spectral analysis as well as by another methods - Poincaré and sequence plots in the first 4 days (26, 27). The cited authors observed up twofold increase in the time and frequency domain HRV parameters, as well as an increase in the size of Poincaré plot reflecting the enhancement of HRV during the early postnatal period. A possible explanation for the increase in HRV may be postnatal acceleration of maturation. Another explanations, which can be done in combination with the first one are 1) an impact of the onset of air breathing after birth with enhancement of the respiratory sinus arrhythmia and 2) gradual withdrawal of postnatal stress. Postconceptional age (PCA): Postconceptional age is calculated as gestational age plus postnatal age (PCA = GA + PNA). It is a function of both, gestational and postnatal ages. HRV in relations to postconceptional age was studied by Yang el. (17). They found thas the postconceptional age advanced, that exerts a significant influence over HRV with a steady increase in total power and in the both LF and HF bands, along with a progressive decline of LF/HF ratio (sympathovagal balance). Newborns of more than 36 weeks PCA demonstrated a significantly greater chronotropic regulatory activity of ANS than the younger group. The maturation of sympathovagal balance needed to take two more weeks with a LF/HF ratio cut-off age occurring at 38 weeks PCA. It means that newborns with PCA more than 38 weeks are relatively mature for neonatal conditions in terms of sympathovagal balance. Gender In adulthood, there are sex differences in the mean heart rate and HRV (e.g. 28). Adult females of childbearing age have a higher HR by 3-7 per min compared with men. Some papers deal the question whether these sex differences in the HR and HRV are already present birth or develop later. The results of the studies on gender differences in HR and HRV in newborns are not uniform. Kero (29) and Yang el. (17) in premature infants, and Harper with co-workers (30) in full term newborns and infants did not find any significant gender differences in heart rate. On the other hand, Javorka and Zavarska (31) and Nagy el. (32) found that boys have, on average, by 5, resp. 7 beats per minute significantly lower mean heart rate compared with girls. Lehotska and Javorka (26, 27) found marginally no significant differences in the average duration of RR intervals: male newborns tended to a higher value of RR intervals (RR intervals in boys: 501 ± 13 ms, in girls: 461 ± 13 ms p = 0.051), i.e. slightly lower mean HR. HRV parameters did not differ between boys and girls. Potential higher heart rate in girls could be associated with distinct morphological and functional parameters of CVS, as the size of the heart, stroke volume, and so, therefore, not only directly related to the endocrine sex differences. Nutrition. Small for Gestational Age (SGA) newborns Nutrition and growth can play important role in cardiovascular system functions. This is why some authors studied in detail the relationship between intrauterine growth reflected in size and weight of newborns and HR/HRV. Spassov el. (32) examined HR and HRV in small for gestational age (SGA) newborns born in 37 - 41 gestational week during sleep. In both, REM as well as NREM, SGA newborns differed from appropriate for gestational age (AGA) newborns by shorter RR intervals (higher mean HR) and reduced HRV in all bands. The parameters of the HR and HRV in SGA newborns are influenced mainly through sympathetictivity in early postnatal period (33). Lehotska el. (34) observed in SGA newborns a tendency for a higher mean heart frequency. Taking into account thau- tonomic nervous system is an important regulator of metabolism and energetic balance and SGA group has higher metabolic rate per kg of weight, these factors can explain physiological role of the higher HR in SGA newborns. Results of time and spectral frequency analysis of the HRV and Poincaré plot in the 1snd 4th postnatal days have shown no differences between SGA and AGA newborns. Significant differences between these two groups in HRV during the first neonatal day of life were found only by sequence plot method (27). Sleep During sleep, significant changes in activities occur not only in CNS, bulso in other systems, including cardiovascular and respiratory. In adults, during NREM sleep, there is usually more regular breathing with unchanged respiratory rate but diminished tidal volumes resulting in higher PaCO2 and a small decrease in PaO2 (by 5 and 2 mmHg on average). In REM sleep, the breathing is irregular and accelerated. Regarding HRV, in adults during NREM compared to REM sleep is a decrease in HRV total power due to reduction of activities in VLF and LF bands. Activity in HF band can be increased, unchanged, or decreased according to hange of breathing pattern. In REM sleep, activity in the VLF and LF bands in contrast to HF rises resulting in significant increase of LF/HF ratio. An interesting finding was found out by Busek el. (36) that the ratio LF/HF increases even just before the onset of REM phase. It indicates potential importance of ANS activity changes for sleep organization, which can be not only an accompanying phenomenon bulso one of the factors causing changes in sleep organization. Influence of sleep stages on HRV in infants was studied by several authors (e.g. 20,21,37). HRV measures are affected by sleep state in different ways. During quiet NREM sleep, newborns had lower mean HR as well as parameters of the HRV compared with awake state (20). However, during REM sleep the HRV parameters were similar to the ,,awake" HRV. Porges el. (21) found in newborns in NREM sleep significantly longer RR intervals but increased amplitude of the HRV mainly in the HF band influenced by respiratory sinus arrhythmia (RSA). Enhancement of the RSA may be related to breathing pattern in non-REM sleep. For quantification nonlinear HRV during different sleep stages used Vandeput el (38) the numerical noise titration technique. Periods of NREM sleep have significantly lower noise limit values, which means that the RR interval series are in this stage less chaotic. The authors state that using this technique of HRV evaluation, periods of NREM sleep can be distinguished from periods of REM sleep and from total recording period. Spontaneous Breathing and Artificial Ventilation Breathing pattern (mainly respiratory rate and depth) greatly affects HR and HRV, especially HF band reflecting respiratory sinus arrhythmia (RSA). RSA as the relationship between breathing and heart rate is a manifestation of physiological regulation of cardiovascular and respiratory systems and their links. In newborns the mean respiratory rate is about 40-60/min and gradually decreases by postnatal age. Often, typically in premature infants is irregular or periodic. The more immature is a newborn the higher is occurrence of the periodic breathing. In a slow and deep breathing is enhanced parasympathetic HF band, which is under the influence of RSA. These changes also occur in newborns who have typical dominanctivity in LF band. Baldzer el. (39) examined the relationship between heart rate and breathing pattern in healthy full term newborns in the first postnatal days during a quiet sleep. For children with lower respiratory rate, RSA accounted for more than 20 % of the total power, and ratio LF/HF was less than 4. The second group of newborns with higher respiratory rate had reduced power in HF band (RSA) and LF/ HF ratio was greater than 4. HRV is affected also by the artificial ventilation, by frequency of ventilation (Fig.2) and tidal volume. Even in premature infants with respiratory distress syndrome (born in 33rd gestational week ) during the first 3 postnatal days, artificial ventilation induced enhancement of HF band (RSA) in spectral HRV (40). This artificially elicited ,,RSA" can occur even in severely immature infants (ase of newborn of gestational age 28.5 weeks, weight 940 g described by Zernikow and Michel; 41). This finding suggests that parasympathetic part of the autonomic nervous system may be in some preterm infants more mature as expected. Fig. 2 Power spectral density (PSD) of HRV in anaesthetized paralyzed rabbirtificially ventilated with frequencies: 1) 30/min (0.5 Hz) and 2) 100/min (1.66 Hz). Frequency of spectral activity (X axis) corresponds to ventilatory frequencies RSA PECULARITIES OF THE CARDIACTIVITY REGULATION IN NEWBORNS Intracardiand extracardiac regulations Regulation of cardiactivity in fetuses and newborns has its own pecularities. All the specificities of the cardiac regulation determine basal heart rate, HRV and heart rate reactions to various stimuli in newborns. Intracardiautoregulation - heterometric (Frank and Starling law) and homeometric (depending on the frequency) is functioning already in fetuses and newborns , but the curve - relationship between end-diastolic volume and myocardial contraction force (Fig. 3) is shifted to the upper limit (42). Therefore, the homeometric mechanism - dependence between heart rate and cardiac output - seems to be more important for cardiac regulation. It follows that changes in heart rate in fetuses and newborns cause relatively more important changes in cardiac output compared with older children and adults. Fig. 3 Relationship curves between end-diastolic volume (EDV) and cardiac output (CO) in newborn, adulnd fetal subjects. Modified from Rudolph (42) Also extracardiac regulation in fetal and early postnatal life is realized with certain pecularities: Baroreflexes are in function in fetuses as well as in newborns, however they are less important in comparison to later postnatal life, and their sensitivity is reduced. Opinions that in the baroreflex sensitivity (BRS) reduction an important role plays immaturity of the baroreflex arre based on the findings that BRS increases with postnatal age faster in term than in preterm infants (43). BRS rises progressively with postnatal age, and in 3rd 6th months (according to maturity at birth) reaches values comparable to the adults (44,45). Chemoreflexes: The fetuses have more active aortic than carotid peripheral chemoreceptors (46). After birth, the start of extrauterine breathing and significant change in PaO2 reset sensitivity of peripheral chemoreceptors to new values of PaO2. This transient state lasts some time (up two weeks). During this lag time physiological role of the peripheral chemoreceptors in regulation of cardiorespiratory functions is diminished and the chemoreceptors become increasingly more oxygen-sensitive. Approximately, by 2 weeks of postnatal age, peripheral chemoreceptor activity is similar to that of adults. Regarding central chemoreceptors - term infants have already adult-like activity at birth, whereas preterm infants take 4 weekes to achieve their level of response (47). Both chemoreceptor types (central and peripheral) are crucial for regulation of breathing, however, the circulation may be influenced, too. This influence is direcnd indirect (through ventilatory changes). Changes in heart rate during stimulation of peripheral chemoreceptors by hypoxia is modified via baroreflexes by hypertensive response due to redistribution of circulating blood. This is why the primary tachycardic response is usually replaced by bradycardia in hypoxia. Cardiac reflexes Pecularities in chronotropic cardiac regulation determined by above described factors influence also complex cardiovascular reflexes in newborns. Evaluation of these reflexes is complicated by absence of voluntary cooperation of examined subjects newborns, and therefore by inability to apply some examination methods normally used in older children and adults: Ewing's battery of cardiovascular tests. From the Ewing's battery, the most proven cardiovascular tests for examination of cardiac chronotropic regulation are deep breathing, orthostatind Valsalva tests. Nevertheless, deep breathing tesnd Valsalva test require voluntary cooperation of the examined subjecnd they cannot be applied in newborns. Rarely, a modified orthostatic test was studied in newborns (48, 49). Passive head up tilting to + 45° and 90° used Andrasyova and Kellerova (50) in full term newborns in postnatal age 1-7 days. From the first day was presenn increase of HR in the orthostasis. The increases of all studied cardiovascular parameters (HR as well as systolind diastolic blood pressure) were present only in 4- to 7-day-old newborns. It seems that the development in the reactivity of cardiovascular system becomes apparenfter a relative stabilization of the neonatal blood volume on the 2nd 3rd postnatal day. Cardiovascular reactions to orthostasis were delayed and prolonged in cocaine-exposed neonates indicating alteration of the development of sympathetind parasympathetic systems after prenatal cocaine exposure (51). In newborns were studied also other cardiovascular tests: cold face test (44), oculocardiand Cushing reflex (52), chronotropic responses accompanying orientation and defense responses (31), etc. Results have shown that healthy newborns can react to various stimuli by heart rate changes according to the degree of developmennd maturity. Unfortunately, methodology, standardization and interpretation of the mentioned CV tests are not well established for neonatology. That is why new methods (for example HRV evaluated in time and frequency domains and by nonlinear methods) that would not require voluntary cooperation of the examined subject should be studied and developed. CONCLUSIONS Heart rate and heart rate variability is determined by many factors. Major factor is heritability followed by ,,tracking phenomenon". Factor of prematurity is demonstrated by higher HR and reduced HRV with significant dominancy of sympathetictivity (LF band in HRV). During the first postnatal days, HRV parameters significantly increase reflecting maturation of the autonomic nervous system and some physiological changes (breathing pattern, etc.). Influence of gender and nutrition (hypotrophy, SGA) on HR and HRV in newborns is not significant, however tendency to higher HR in girls and in SGan be seen. In NREM sleep are significantly longer RR intervals and enhanced HRV mainly in parasympathetic HF band (reflecting respiratory sinus arrhythmia - RSA) in relation to changed breathing pattern. Respiratory rate and tidal volumes during spontaneous breathing affect HR and spectral activity in HRV - HF band. It can be seen also during artificial ventilation of newborns. Regulation of cardiactivity in newborns has its own specific features. Dominant mechanism in autoregulation is mechanism depending on the heart rate. Baroreflexes in newborns have reduced sensitivity (BRS), which rises progressively with postnatal age. The values of BRS for preterm newborns are lower than the values for full term babies. Newborns have active cardiovascular reflexes for maintaining of adequate perfusion of organs according to conditions. Maturation of the cardiovascular regulation in early postnatal period is reflected in changes of some reflexes like of the orthostatic reflex.
Acta Medica Martiniana – de Gruyter
Published: Aug 1, 2011
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