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Effects of birth weight on spontaneous baroreflex sensitivity in adult life
Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 303e310
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Effects of birth weight on spontaneous baroreflex sensitivity in adult life* Giannina Leotta*, Franco Rabbia, Alberto Milan, Paolo Mulatero, Franco Veglio Divisione di Medicina Interna e Ipertensione, Ospedale S. Vito, Universita` di Torino, Strada S. Vito 34, 10133 Turin, Italy Received 16 May 2005; received in revised form 21 July 2005; accepted 28 September 2005
KEYWORDS Barker hypothesis; Birth weight; Spontaneous baroreflex sensitivity; Hypertension
Abstract Background and aim: Several epidemiological studies have suggested a link between low birth weight and coronary heart disease; this may be partly due to the association between low birth weight and conventional risk factors. Among the factors involved in the regulation of cardiovascular homeostasis, baroreflexes play a crucial role. The objective of the present study was to investigate if baroreflex sensitivity (BRS) in adulthood is associated with birth weight. Methods and results: Two hundred and eleven adults from Turin, Italy, aged 22e 24 years, were examined in a cross sectional survey. Birth weight, blood pressure, pulse rate, family history of hypertension, anthropometric and environmental parameters and spontaneous baroreflex sensitivity were evaluated. In this study we observed a significant increase in baroreflex sensitivity across the tertiles of birth weight, even after correction for gender, blood pressure and heart rate; in a regression model, birth weight was positively and independently associated with BRS; moreover, BRS showed a significant negative correlation with adult pulse rate. Conclusion: This finding may be helpful in understanding the association between low birth weight and cardiovascular disease outcome in later life, since baroreflex failure is associated with an increased cardiovascular morbidity and mortality. ª 2006 Elsevier B.V. All rights reserved.
Introduction *
This work was supported by a grant (19.700/27.001) of Regione Piemonte. * Corresponding author. Tel.: þ39 011 660 4900; fax: þ39 011 660 2707. E-mail address: [email protected] (G. Leotta).
Several epidemiological studies have suggested a link between low birth weight and coronary heart disease; this may be partly due to the association between low birth weight and conventional risk factors [1e8]. The development of
0939-4753/$ - see front matter ª 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2005.09.008
304 hypertension, diabetes, and other risk factors for atherosclerosis may be related to adaptive measures undertaken by the foetus. The inverse relationship between birth weight and subsequent blood pressure has been considered to provide the most consistent support for the ‘‘foetal origin’’ hypothesis of adult disease. However, the mechanism underlying the development of coronary heart disease in adult life from restricted foetal growth is unknown. Changes in the autonomic nervous system are involved in the development of both high blood pressure and the metabolic syndrome. Recently, low birth weight has been associated with increased sympathetic activity, and this association has been suggested to be dependent on genetic factors [9]. Among the factors involved in the regulation of cardiovascular homeostasis, arterial baroreflex plays a crucial role in short-term regulation of blood pressure and heart rate [10]. Carotid and aortic baroreceptors sense changes in stretch that result from alterations of blood pressure. The signal generated in these receptors travels to cardiovascular control centres in the brain stem. This afferent input results in counter regulatory adjustments of sympathetic and parasympathetic tone and prevents excessive fluctuations in blood pressure. Baroreceptor modulation of heart rate is impaired in hypertensive subjects. Although it is difficult to establish the causal role of the baroreflex abnormality in essential hypertension, a depressed baroreflex sensitivity may be involved in target organ damage and adverse outcome [11e13]. Furthermore, disturbances of baroreflex have been associated with increased cardiovascular morbidity and mortality [14,15]. The definition of the mechanisms that affect baroreflex function could help the understanding of cardiovascular disease. Several epidemiological studies suggest that spontaneous baroreflex sensitivity is influenced by gender, body mass, and genetic factors [16,17]. Moreover, in experimental studies, arterial baroreflex control of heart rate has been found to be blunted in Wistar rats subject to protein deprivation during the foetal period and in young adult sheep that underwent global energy restriction during early gestation [18,19]. To date, no studies have investigated the effects of foetal and childhood growth on spontaneous baroreflex function in humans. The purpose of this study was to test whether spontaneous baroreflex sensitivity (BRS), measured in a cohort of healthy young adults, is influenced by foetal growth.
G. Leotta et al.
Methods Sample The study was part of an extensive survey conducted in order to describe the distribution of atherosclerosis risk factors from adolescence to adulthood [20]. The population consisted of 211 healthy subjects (98 males, 113 females) randomly selected from the original sample. Ninety-five percent of the selected subjects participated to the study: three of the selected subjects had died in car accidents, one was excluded from the study due to diabetes. All subjects were evaluated twice 10 years apart; the first visit was done between 1991 and 1992, at ages 12e14, and the second between 2001 and 2002, at ages 22e24. The sample was enrolled in public junior high schools of Turin, choosing one school for each of the 23 residential areas. Adolescent examinations were conducted in the schools. Adult examinations were conducted in our outpatient clinic. Subjects were examined in the morning after fasting and refraining from smoking and heavy physical activity. The studied population consisted of Caucasians; none took antihypertensive or hormonal drugs; females taking oral contraceptives were included. At each examination we evaluated blood pressure, pulse rate, anthropometric and environmental parameters. Baroreflex sensitivity was evaluated only at the second examination. The investigation conforms with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the local ethics committee. In children, written informed consent was obtained from both parents or from a legal guardian, and verbal informed consent was obtained from the children. In adulthood, written informed consent was obtained from the subjects examined.
Variables measured Height was measured to the nearest 0.1 cm with the subjects barefoot using a manual height board. Weight was measured with subjects barefoot and without clothes, using an electronic scale. At the first examination, we calculated degree of sexual development according to Tanner indices [21]. Children were classified into three groups: A (low sexual development, corresponding to Tanner stage 1), B (intermediate sexual development, corresponding to Tanner stage 2e3), C (complete sexual development, corresponding to Tanner stage 4e5).
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Gestational age and birth weight were obtained from routine medical records. The subjects were classified as pre-term, term, and post-term born according to Gairdner and Pearson charts. Physical fitness was recorded as weekly hours of sport or play activity during adolescence. By contrast, in adulthood we considered as high physical activity when done at least once a week (coded as 1) and the other conditions as low physical activity (coded as 0). As an index of sedentariness during childhood, we calculated the number of hours a day spent watching television. Smoking was recorded as the number of cigarettes smoked daily. Alcohol consumption was converted into grams of alcohol per day. We recorded family history of high blood pressure at each examination, either by questionnaire (answered by parents) or by structured interview. Blood pressure status of first-degree relatives (parents) was defined. At the first examination, blood pressure was measured according to the ‘‘Second Task Force on blood pressure control in children’’ [22], that is, with children in a comfortable sitting position with the right arm fully exposed and resting on a supportive surface at the heart level; we used a mercury sphygmomanometer (Erkameter) with appropriate-size cuff and took three measurements after 5, 10 and 15 min of sitting position. Systolic blood pressure was recorded at first phase and diastolic blood pressure at fifth phase of Korotkoff sounds. The mean of three blood pressure measurements was considered in the study. At the second examination, after 20 min of supine rest in a quiet room, we measured blood pressure three times on the right arm, after 5, 10 and 15 min of sitting position, using the oscillometric device AND-UA631. The mean of the three measurements was considered. Calibration controls were carried out at weekly intervals against a mercury sphygmomanometer using the classical T system for simultaneous determinations. At each examination, we measured pulse (radial) rate three times after 5, 10 and 15 min in the sitting position and calculated the mean of the three measurements.
We assessed spontaneous baroreflex sensitivity by the time domain method for the evaluation of spontaneous baroreflex control of heart rate; this method has been validated and described in detail by Parati [25]. This evaluation is based on the computerized analysis of spontaneous fluctuations in systolic blood pressure and of the associated reflex fluctuations in pulse interval (the reciprocal of heart rate). Briefly, it consists of computer scanning of the tracing of systolic blood pressure to identify sequences of 4 consecutive beats, characterized by a progressive increase in systolic blood pressure and a linearly related increase in pulse interval (correlation coefficient, r 0.85), or by a progressive reduction in systolic blood pressure accompanied by a linearly related (r 0.85) decrease in pulse interval. The slope of the regression line between pulse interval and systolic blood pressure values within each sequence was taken as an index of baroreflex sensitivity. We computed spontaneous baroreflex sensitivity over periods of at least 10 min to obtain a high reproducibility of data, as described previously [26].
Spontaneous baroreflex control of heart rate Continuous finger blood pressure was recorded by a Portapres Model-2 device (TNO, Amsterdam, NL) at 200 Hz sampling frequency in the supine position for 30 min [23,24]. This evaluation was conducted immediately after blood pressure and pulse rate recording.
Statistical analysis Statistical analysis was performed using the Statistical Analysis Package (SAS) [27]. We calculated means and standard deviations of descriptive statistics. Student t-test and c2 were used to compare continuous and categorical variables, respectively. The normality of the distribution of the parameters studied was tested with KolmogrooveSmirnov analysis. The power of this study is 80% with a 5% significance level. To investigate the relationship between birth weight and spontaneous baroreflex sensitivity, we compared the values of BRS observed in different tertiles of birth at weight by performing a one-way ANOVA with Bonferroni correction for multiple comparison. We then compared the subjects in the lower tertile of birth weight both with all the other subjects and with a group matched for age, gender, adult weight, blood pressure values and pulse rate. Moreover, we performed a multiple regression analysis to explain baroreflex sensitivity (dependent variable, expressed on a logarithmic scale in order to obtain a normal distribution of the values) as a function of the biological and environmental variables evaluated. We built the model, firstly introducing birth weight, then progressively introducing the following parameters: gestational age, weight and height in adolescence, gender, degree of sexual development in adolescence,
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weight and height in adulthood, blood pressure and pulse rate in adolescence and adulthood, physical fitness in adolescence and adulthood, sedentariness in adolescence, smoking and drinking habits in adulthood, and finally family history of high blood pressure. Following the suggestions of Fewtrell and Cole [3], in order to better evaluate the effect of birth weight on spontaneous baroreflex sensitivity, we tested for interaction of the adolescent and adult weight in the regression analysis.
Results In Table 1, general characteristics of the study population are summarized. We found a significant but small difference in birth weight between males and females (3.3 kg in males vs. 3.2 kg in females). In adolescence males are significantly taller and show higher values of blood pressure, and a higher degree of physical activity and sexual development than females. In adulthood, height, weight,
Table 1
blood pressure, and percentage of smokers are significantly higher in males, while females show a significantly faster pulse rate. As shown in Fig. 1, BRS values significantly increase across the tertiles of birth weight (from 20.25 ms/mmHg in the lower tertile to 26.71 ms/ mmHg in the higher one, p ¼ 0.0062); the differences are conserved and statistically significant after correction for gender, blood pressure and heart rate (p ¼ 0.012). Moreover, the subjects in the lower tertile of birth weight show a significantly reduced BRS as compared with the other subjects (20.25 7.87 mmHg vs. 25.88 11.48 mmHg, p ¼ 0.002), even after correction for gender, blood pressure and pulse rate (p ¼ 0.0058). The difference in baroreflex sensitivity between the subjects in the lower tertile of birth weight and the others is enhanced after comparison with a group of subjects matched for age, gender, adult weight, SBP, DBP and pulse rate (BRS ¼ 20.25 7.95 ms/mmHg in the lower tertile vs. 26.62 12.63 ms/mmHg in the matched group, p ¼ 0.0032).
General characteristics of the population studied Males (n ¼ 98)
Birth weight (kg) Adolescent characteristics Age (years) Height (cm) Weight (kg) Tanner stage (%)b A B C Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse rate (beats/min) Physical activity (h/week) TV (h/day) Adult characteristics Age (years) Height (cm) Weight (kg) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse rate (beats/min) Baroreflex sensitivity Smoking (cigarettes/day) Alcohol (g/day) Oral contraceptives (%) Physical activity (%) High Low
3.3 0.6
Females (n ¼ 113)
pa
3.2 0.5
0.04
13.4 0.6 158.6 9.0 49.5 10.2
13.4 0.8 155.3 6.6 47.3 8.8
0.41 0.01 0.15
10.0% 33.3% 56.7% 114.9 11.2 64.8 11.2 79.5 7.9 5.2 3.1 3.0 1.2
9.6% 56.2% 34.3% 109.1 10.7 61.5 10.7 81.5 10.5 4.0 2.5 2.9 1.3
0.01
23.5 0.7 175.1 7.5 73.1 12.3 128.2 13.9 73.2 9.1 72.3 12.7 22.7 9.4 7.1 10.1 6.0 16.3
23.5 0.8 161.2 6.4 56.1 8.9 111.5 10.6 70.0 8.8 77.6 10.6 25.4 11.7 2.8 5.0 2.5 8.2 34.5%
49.3% 50.7%
44.4% 55.6%
Values are mean standard deviation, or percentage (%). a p value for differences between sexes, calculated with Student t-test or c2. b A, low sexual development; B, intermediate sexual development; C, complete sexual development.
0.001 0.05 0.19 0.008 0.41 p 0.34 <0.0001 <0.0001 <0.0001 0.03 0.005 0.16 0.0005 0.08
0.53
Effects of birth weight on spontaneous baroreflex §
Baroreflex sensitivity (ms/mmHg)
35
*
30
26.71±11.47 25.19±11.53
25 20.25±7.87 20 15 10 5 0 Lower
Median
307 related to potential extravascular effects of vasoactive agents [28]. Spontaneous baroreflex assessment by the sequence method is significantly correlated with BRS values provided by vasoactive drug injection and, because of its feasibility, may be ideal for large studies [16,29]. In recent studies, non-invasive measurement of spontaneous baroreflex sensitivity was significantly and independently related with several cardiovascular risk factors, so that it has been proposed as a variable integrating the effect over time of several classical risk factors on the cardiovascular system [14,30].
Upper
Tertiles of birth at weight
Figure 1 Baroreflex sensitivity (BRS) in different birth weight tertiles. p ¼ 0.0062 for comparison between the three groups (ANOVA). Values are mean standard deviation. *p < 0.05 for comparison between the two tertiles. xp < 0.01 for comparison between the two tertiles (Bonferroni correction for multiple comparison).
Table 2 shows the results of the regression analysis performed to explain baroreflex sensitivity (expressed on a logarithmic scale) as a function of birth weight and the other variables evaluated during adolescence and adulthood. In a simple regression analysis (model 1) a significant positive relationship exists between birth weight and baroreflex sensitivity (b ¼ 0.16, p < 0.008, R2 ¼ 0.04). This relationship is unchanged after adjustment for all possible confounders (gestational age, anthropometric variables, systolic and diastolic blood pressure, pulse rate, environmental variables, and family history of hypertension), as shown in the full model (b ¼ 0.15, p ¼ 0.03, R2 ¼ 0.05). Moreover, a significant negative relationship exists between baroreflex sensitivity and adult pulse rate (b ¼ 0.01, p ¼ 0.002, R2 ¼ 0.12).
Discussion In this study we observed a significant increase in baroreflex sensitivity across the tertiles of birth weight, even after correction for gender, blood pressure and heart rate; a multiple regression analysis demonstrated a positive independent association between birth weight and spontaneous baroreflex sensitivity; in addition to that, baroreflex sensitivity was significantly associated with adult pulse rate, as previously observed [14,16]. To assess baroreflex sensitivity, we used the spontaneous sequence method, which is currently employed, being an easy and practical method that minimizes risk and circumvents the problems
Mechanisms and implications Spontaneous baroreflex sensitivity reflects the cardiac parasympathetic modulation of heart rate, which may be linked to birth weight through several mechanisms. In general, cardiac baroreceptor reflex can be modulated at different levels, namely at the afferent, central or efferent components of the reflex arch. On the basis of previous findings, an effect of foetal growth on the afferent limb of the reflex arch can be hypothesized: an increased carotid intima-media thickness has been demonstrated in subjects with a lower birth weight in whom increased susceptibility to atherogenesis may come from endothelial dysfunction caused by malnutrition in the uterus [31]. In turn, greater intima media thickness in the carotid bulb, an area with an high density of baroreceptors, may contribute to reduce baroreflex sensitivity by increasing vascular stiffness, so that a higher pressure threshold is required to distend the arterial wall. Indeed, a negative relationship between carotid intima media thickness and baroreflex sensitivity has been recently demonstrated [32]. An increased arterial stiffness has also been attributed to impaired elastin synthesis in arterial walls, caused by haemodynamic changes in the foetal circulation that occur in foetuses showing retarded growth [33]. Moreover, it has been demonstrated that the serum of undernourished rats affects the proliferation of cultured vascular smooth muscle cells [34]. Centrally, neurohormonal changes that influence baroreflex efferent autonomic pathway as well as activation of other neural reflex pathways are potential factors that may be modified in foetal nutrient deprivation [35]. An impaired foetal growth may reduce baroreflex sensitivity by activating on the renineangiotensin system, therefore affecting the central nervous processing of baroreceptor afferent signals or the efferent limb of the reflex arch. This mechanism has been
308 Table 2
G. Leotta et al. Linear regression analysis of baroreflex sensitivity (expressed on a logarithmic scale)
Independent variables
Baroreflex sensitivity Model 1
Intercept Birth weight (kg) Gestational agea Adolescent weight (kg) Adolescent height (cm) Sexual developmentb Adult weight (kg) Adult height (cm) Adolescent weight/adult weight interaction Adolescent systolic blood pressure (mmHg) Adolescent diastolic blood pressure (mmHg) Adolescent pulse rate (beats/min) Adult systolic blood pressure (mmHg) Adult diastolic blood pressure (mmHg) Adult pulse rate (mmHg) Adolescent sport (h/week) Adolescent TV (h/day) Adult sportc Smoking habits (cigarettes/day) Alcohol consumption (g/day) Family history of hypertensiond
Full model 2
b (p)
R
2.57 (<0.0001) 0.16 (0.008)
0.04
Partial R2
b (p) 5.87 0.15 0.0005 0.007 0.007 0.04 0.02 0.001 0.0002 0.0005 0.004 0.005 0.002 0.001 0.01 0.02 0.06 0.04 0.0006 0.001 0.07
(<0.0001) (0.03) (0.99) (0.67) (0.31) (0.53) (0.22) (0.85) (0.51) (0.90) (0.18) (0.18) (0.66) (0.84) (0.002) (0.10) (0.03) (0.57) (0.89) (0.70) (0.27)
0.05 0 0.02 0.008 0.002 0.01 0.03 0.003 0.0001 0.02 0.008 0.001 0.0001 0.12 0.01 0.02 0.003 0.0001 0.0008 0.008
Model 1: unadjusted. Full model: adjusted for gestational age, adolescent weight, adolescent height, sexual development, adult weight, adult height, interaction adolescent weight/adult weight, adolescent blood pressure, adolescent heart rate, adult blood pressure, adult HR, adolescent sport and TV, adult smoking habits, alcohol consumption, sport and hypertensive familiarity. Adjusted R2 for full model ¼ 0.22. a 0, preterm born; 1, term born. b 0, low sexual development; 1, intermediate sexual development; 2, complete sexual development. c 0, high physical activity; 1, low physical activity (see text for explanation). d 0, no; 1, yes (see text for explanation).
hypothesized in a recent experimental study conducted on the adult offspring of Wistar rats: in the animals subjected to protein deprivation during the foetal period, a reduced arterial baroreflex control of heart rate, an increased blood pressure variability and an enhanced expression of brain AT(1) receptors was observed [18]. Similarly, periimplantation global underfeeding has been found to blunt baroreflex control of heart rate during angiotensin II infusion in young adult sheep [19]. In our study, only the baroreflex modulation of the efferent cardiovagal effector mechanism has been evaluated. However, since baroreceptors are also involved in the control of sympathetic nerve traffic, reduced baroreflex sensitivity could explain the increased sympathetic activity recently found in subjects with low birth weight [9,36].
Perspectives This work shows a positive relationship between birth weight and spontaneous baroreflex sensitivity
in young adults. The strength of the association may be more evident in subjects with low birth weight. We cannot compare it to similar studies since, to our knowledge, the effect of foetal growth on baroreflex function in human beings has not been investigated to date. However, our finding is consistent with the results of a recent experimental study performed on Wistar rats, in which arterial baroreflex control of heart rate was reduced in the case of protein deprivation during the foetal period [17]. Similarly, peri-implantation global underfeeding has been found to blunt baroreflex control of heart rate during angiotensin II infusion in young adult sheep [18]. It may be hypothesized that reduced baroreflex sensitivity in low birth weight subjects represents a link between foetal growth and cardiovascular disease since, in epidemiological studies, both low birth weight and baroreflex abnormalities have been associated with an increased cardiovascular morbidity and mortality.
Effects of birth weight on spontaneous baroreflex
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Further studies will need to unravel the relationship between foetal growth, baroreflex sensitivity and cardiovascular morbidity, and to clarify whether an improvement in foetal nutrition might contribute towards preventing adult disease.
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Acknowledgements This work was supported by a grant (19.700/ 27.001) of Regione Piemonte. We thank Turin General practitioners for their invaluable help in recalling the population studied ten years later.
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310 measurements of baroreflex sensitivity. Implications for studies on risk stratification after a myocardial infarction. Eur Heart J 2000;21:1522e9. doi:10.1053/euhj. 1999.1948. [31] Gale CR, Ashurst HE, Hall NF, MacCallum PK, Martyn CN. Size at birth and carotid atherosclerotic in later life. Atherosclerosis 2002;163:141e7. doi:10.1016/S0021-9150 (01)00760-2. [32] Gianaros PJ, Jennings JR, Olafsson B, Steptoe A, SuttonTyrrell K, Muldoon MF, et al. Greater intima-media thickness in the carotid bulb is associated with reduced baroreflex sensitivity. Am J Hypertens 2002;15:486e91. doi: 10.1016/S0895-7061(02)02923-0. [33] Martyn CN, Greenwald SE. Impaired synthesis of elastin in walls of aorta and large conduit arteries during early
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Effects of birth weight on spontaneous baroreflex sensitivity in adult life* Giannina Leotta*, Franco Rabbia, Alberto Milan, Paolo Mulatero, Franco Veglio Divisione di Medicina Interna e Ipertensione, Ospedale S. Vito, Universita` di Torino, Strada S. Vito 34, 10133 Turin, Italy Received 16 May 2005; received in revised form 21 July 2005; accepted 28 September 2005
KEYWORDS Barker hypothesis; Birth weight; Spontaneous baroreflex sensitivity; Hypertension
Abstract Background and aim: Several epidemiological studies have suggested a link between low birth weight and coronary heart disease; this may be partly due to the association between low birth weight and conventional risk factors. Among the factors involved in the regulation of cardiovascular homeostasis, baroreflexes play a crucial role. The objective of the present study was to investigate if baroreflex sensitivity (BRS) in adulthood is associated with birth weight. Methods and results: Two hundred and eleven adults from Turin, Italy, aged 22e 24 years, were examined in a cross sectional survey. Birth weight, blood pressure, pulse rate, family history of hypertension, anthropometric and environmental parameters and spontaneous baroreflex sensitivity were evaluated. In this study we observed a significant increase in baroreflex sensitivity across the tertiles of birth weight, even after correction for gender, blood pressure and heart rate; in a regression model, birth weight was positively and independently associated with BRS; moreover, BRS showed a significant negative correlation with adult pulse rate. Conclusion: This finding may be helpful in understanding the association between low birth weight and cardiovascular disease outcome in later life, since baroreflex failure is associated with an increased cardiovascular morbidity and mortality. ª 2006 Elsevier B.V. All rights reserved.
Introduction *
This work was supported by a grant (19.700/27.001) of Regione Piemonte. * Corresponding author. Tel.: þ39 011 660 4900; fax: þ39 011 660 2707. E-mail address: [email protected] (G. Leotta).
Several epidemiological studies have suggested a link between low birth weight and coronary heart disease; this may be partly due to the association between low birth weight and conventional risk factors [1e8]. The development of
0939-4753/$ - see front matter ª 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2005.09.008
304 hypertension, diabetes, and other risk factors for atherosclerosis may be related to adaptive measures undertaken by the foetus. The inverse relationship between birth weight and subsequent blood pressure has been considered to provide the most consistent support for the ‘‘foetal origin’’ hypothesis of adult disease. However, the mechanism underlying the development of coronary heart disease in adult life from restricted foetal growth is unknown. Changes in the autonomic nervous system are involved in the development of both high blood pressure and the metabolic syndrome. Recently, low birth weight has been associated with increased sympathetic activity, and this association has been suggested to be dependent on genetic factors [9]. Among the factors involved in the regulation of cardiovascular homeostasis, arterial baroreflex plays a crucial role in short-term regulation of blood pressure and heart rate [10]. Carotid and aortic baroreceptors sense changes in stretch that result from alterations of blood pressure. The signal generated in these receptors travels to cardiovascular control centres in the brain stem. This afferent input results in counter regulatory adjustments of sympathetic and parasympathetic tone and prevents excessive fluctuations in blood pressure. Baroreceptor modulation of heart rate is impaired in hypertensive subjects. Although it is difficult to establish the causal role of the baroreflex abnormality in essential hypertension, a depressed baroreflex sensitivity may be involved in target organ damage and adverse outcome [11e13]. Furthermore, disturbances of baroreflex have been associated with increased cardiovascular morbidity and mortality [14,15]. The definition of the mechanisms that affect baroreflex function could help the understanding of cardiovascular disease. Several epidemiological studies suggest that spontaneous baroreflex sensitivity is influenced by gender, body mass, and genetic factors [16,17]. Moreover, in experimental studies, arterial baroreflex control of heart rate has been found to be blunted in Wistar rats subject to protein deprivation during the foetal period and in young adult sheep that underwent global energy restriction during early gestation [18,19]. To date, no studies have investigated the effects of foetal and childhood growth on spontaneous baroreflex function in humans. The purpose of this study was to test whether spontaneous baroreflex sensitivity (BRS), measured in a cohort of healthy young adults, is influenced by foetal growth.
G. Leotta et al.
Methods Sample The study was part of an extensive survey conducted in order to describe the distribution of atherosclerosis risk factors from adolescence to adulthood [20]. The population consisted of 211 healthy subjects (98 males, 113 females) randomly selected from the original sample. Ninety-five percent of the selected subjects participated to the study: three of the selected subjects had died in car accidents, one was excluded from the study due to diabetes. All subjects were evaluated twice 10 years apart; the first visit was done between 1991 and 1992, at ages 12e14, and the second between 2001 and 2002, at ages 22e24. The sample was enrolled in public junior high schools of Turin, choosing one school for each of the 23 residential areas. Adolescent examinations were conducted in the schools. Adult examinations were conducted in our outpatient clinic. Subjects were examined in the morning after fasting and refraining from smoking and heavy physical activity. The studied population consisted of Caucasians; none took antihypertensive or hormonal drugs; females taking oral contraceptives were included. At each examination we evaluated blood pressure, pulse rate, anthropometric and environmental parameters. Baroreflex sensitivity was evaluated only at the second examination. The investigation conforms with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the local ethics committee. In children, written informed consent was obtained from both parents or from a legal guardian, and verbal informed consent was obtained from the children. In adulthood, written informed consent was obtained from the subjects examined.
Variables measured Height was measured to the nearest 0.1 cm with the subjects barefoot using a manual height board. Weight was measured with subjects barefoot and without clothes, using an electronic scale. At the first examination, we calculated degree of sexual development according to Tanner indices [21]. Children were classified into three groups: A (low sexual development, corresponding to Tanner stage 1), B (intermediate sexual development, corresponding to Tanner stage 2e3), C (complete sexual development, corresponding to Tanner stage 4e5).
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Gestational age and birth weight were obtained from routine medical records. The subjects were classified as pre-term, term, and post-term born according to Gairdner and Pearson charts. Physical fitness was recorded as weekly hours of sport or play activity during adolescence. By contrast, in adulthood we considered as high physical activity when done at least once a week (coded as 1) and the other conditions as low physical activity (coded as 0). As an index of sedentariness during childhood, we calculated the number of hours a day spent watching television. Smoking was recorded as the number of cigarettes smoked daily. Alcohol consumption was converted into grams of alcohol per day. We recorded family history of high blood pressure at each examination, either by questionnaire (answered by parents) or by structured interview. Blood pressure status of first-degree relatives (parents) was defined. At the first examination, blood pressure was measured according to the ‘‘Second Task Force on blood pressure control in children’’ [22], that is, with children in a comfortable sitting position with the right arm fully exposed and resting on a supportive surface at the heart level; we used a mercury sphygmomanometer (Erkameter) with appropriate-size cuff and took three measurements after 5, 10 and 15 min of sitting position. Systolic blood pressure was recorded at first phase and diastolic blood pressure at fifth phase of Korotkoff sounds. The mean of three blood pressure measurements was considered in the study. At the second examination, after 20 min of supine rest in a quiet room, we measured blood pressure three times on the right arm, after 5, 10 and 15 min of sitting position, using the oscillometric device AND-UA631. The mean of the three measurements was considered. Calibration controls were carried out at weekly intervals against a mercury sphygmomanometer using the classical T system for simultaneous determinations. At each examination, we measured pulse (radial) rate three times after 5, 10 and 15 min in the sitting position and calculated the mean of the three measurements.
We assessed spontaneous baroreflex sensitivity by the time domain method for the evaluation of spontaneous baroreflex control of heart rate; this method has been validated and described in detail by Parati [25]. This evaluation is based on the computerized analysis of spontaneous fluctuations in systolic blood pressure and of the associated reflex fluctuations in pulse interval (the reciprocal of heart rate). Briefly, it consists of computer scanning of the tracing of systolic blood pressure to identify sequences of 4 consecutive beats, characterized by a progressive increase in systolic blood pressure and a linearly related increase in pulse interval (correlation coefficient, r 0.85), or by a progressive reduction in systolic blood pressure accompanied by a linearly related (r 0.85) decrease in pulse interval. The slope of the regression line between pulse interval and systolic blood pressure values within each sequence was taken as an index of baroreflex sensitivity. We computed spontaneous baroreflex sensitivity over periods of at least 10 min to obtain a high reproducibility of data, as described previously [26].
Spontaneous baroreflex control of heart rate Continuous finger blood pressure was recorded by a Portapres Model-2 device (TNO, Amsterdam, NL) at 200 Hz sampling frequency in the supine position for 30 min [23,24]. This evaluation was conducted immediately after blood pressure and pulse rate recording.
Statistical analysis Statistical analysis was performed using the Statistical Analysis Package (SAS) [27]. We calculated means and standard deviations of descriptive statistics. Student t-test and c2 were used to compare continuous and categorical variables, respectively. The normality of the distribution of the parameters studied was tested with KolmogrooveSmirnov analysis. The power of this study is 80% with a 5% significance level. To investigate the relationship between birth weight and spontaneous baroreflex sensitivity, we compared the values of BRS observed in different tertiles of birth at weight by performing a one-way ANOVA with Bonferroni correction for multiple comparison. We then compared the subjects in the lower tertile of birth weight both with all the other subjects and with a group matched for age, gender, adult weight, blood pressure values and pulse rate. Moreover, we performed a multiple regression analysis to explain baroreflex sensitivity (dependent variable, expressed on a logarithmic scale in order to obtain a normal distribution of the values) as a function of the biological and environmental variables evaluated. We built the model, firstly introducing birth weight, then progressively introducing the following parameters: gestational age, weight and height in adolescence, gender, degree of sexual development in adolescence,
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weight and height in adulthood, blood pressure and pulse rate in adolescence and adulthood, physical fitness in adolescence and adulthood, sedentariness in adolescence, smoking and drinking habits in adulthood, and finally family history of high blood pressure. Following the suggestions of Fewtrell and Cole [3], in order to better evaluate the effect of birth weight on spontaneous baroreflex sensitivity, we tested for interaction of the adolescent and adult weight in the regression analysis.
Results In Table 1, general characteristics of the study population are summarized. We found a significant but small difference in birth weight between males and females (3.3 kg in males vs. 3.2 kg in females). In adolescence males are significantly taller and show higher values of blood pressure, and a higher degree of physical activity and sexual development than females. In adulthood, height, weight,
Table 1
blood pressure, and percentage of smokers are significantly higher in males, while females show a significantly faster pulse rate. As shown in Fig. 1, BRS values significantly increase across the tertiles of birth weight (from 20.25 ms/mmHg in the lower tertile to 26.71 ms/ mmHg in the higher one, p ¼ 0.0062); the differences are conserved and statistically significant after correction for gender, blood pressure and heart rate (p ¼ 0.012). Moreover, the subjects in the lower tertile of birth weight show a significantly reduced BRS as compared with the other subjects (20.25 7.87 mmHg vs. 25.88 11.48 mmHg, p ¼ 0.002), even after correction for gender, blood pressure and pulse rate (p ¼ 0.0058). The difference in baroreflex sensitivity between the subjects in the lower tertile of birth weight and the others is enhanced after comparison with a group of subjects matched for age, gender, adult weight, SBP, DBP and pulse rate (BRS ¼ 20.25 7.95 ms/mmHg in the lower tertile vs. 26.62 12.63 ms/mmHg in the matched group, p ¼ 0.0032).
General characteristics of the population studied Males (n ¼ 98)
Birth weight (kg) Adolescent characteristics Age (years) Height (cm) Weight (kg) Tanner stage (%)b A B C Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse rate (beats/min) Physical activity (h/week) TV (h/day) Adult characteristics Age (years) Height (cm) Weight (kg) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse rate (beats/min) Baroreflex sensitivity Smoking (cigarettes/day) Alcohol (g/day) Oral contraceptives (%) Physical activity (%) High Low
3.3 0.6
Females (n ¼ 113)
pa
3.2 0.5
0.04
13.4 0.6 158.6 9.0 49.5 10.2
13.4 0.8 155.3 6.6 47.3 8.8
0.41 0.01 0.15
10.0% 33.3% 56.7% 114.9 11.2 64.8 11.2 79.5 7.9 5.2 3.1 3.0 1.2
9.6% 56.2% 34.3% 109.1 10.7 61.5 10.7 81.5 10.5 4.0 2.5 2.9 1.3
0.01
23.5 0.7 175.1 7.5 73.1 12.3 128.2 13.9 73.2 9.1 72.3 12.7 22.7 9.4 7.1 10.1 6.0 16.3
23.5 0.8 161.2 6.4 56.1 8.9 111.5 10.6 70.0 8.8 77.6 10.6 25.4 11.7 2.8 5.0 2.5 8.2 34.5%
49.3% 50.7%
44.4% 55.6%
Values are mean standard deviation, or percentage (%). a p value for differences between sexes, calculated with Student t-test or c2. b A, low sexual development; B, intermediate sexual development; C, complete sexual development.
0.001 0.05 0.19 0.008 0.41 p 0.34 <0.0001 <0.0001 <0.0001 0.03 0.005 0.16 0.0005 0.08
0.53
Effects of birth weight on spontaneous baroreflex §
Baroreflex sensitivity (ms/mmHg)
35
*
30
26.71±11.47 25.19±11.53
25 20.25±7.87 20 15 10 5 0 Lower
Median
307 related to potential extravascular effects of vasoactive agents [28]. Spontaneous baroreflex assessment by the sequence method is significantly correlated with BRS values provided by vasoactive drug injection and, because of its feasibility, may be ideal for large studies [16,29]. In recent studies, non-invasive measurement of spontaneous baroreflex sensitivity was significantly and independently related with several cardiovascular risk factors, so that it has been proposed as a variable integrating the effect over time of several classical risk factors on the cardiovascular system [14,30].
Upper
Tertiles of birth at weight
Figure 1 Baroreflex sensitivity (BRS) in different birth weight tertiles. p ¼ 0.0062 for comparison between the three groups (ANOVA). Values are mean standard deviation. *p < 0.05 for comparison between the two tertiles. xp < 0.01 for comparison between the two tertiles (Bonferroni correction for multiple comparison).
Table 2 shows the results of the regression analysis performed to explain baroreflex sensitivity (expressed on a logarithmic scale) as a function of birth weight and the other variables evaluated during adolescence and adulthood. In a simple regression analysis (model 1) a significant positive relationship exists between birth weight and baroreflex sensitivity (b ¼ 0.16, p < 0.008, R2 ¼ 0.04). This relationship is unchanged after adjustment for all possible confounders (gestational age, anthropometric variables, systolic and diastolic blood pressure, pulse rate, environmental variables, and family history of hypertension), as shown in the full model (b ¼ 0.15, p ¼ 0.03, R2 ¼ 0.05). Moreover, a significant negative relationship exists between baroreflex sensitivity and adult pulse rate (b ¼ 0.01, p ¼ 0.002, R2 ¼ 0.12).
Discussion In this study we observed a significant increase in baroreflex sensitivity across the tertiles of birth weight, even after correction for gender, blood pressure and heart rate; a multiple regression analysis demonstrated a positive independent association between birth weight and spontaneous baroreflex sensitivity; in addition to that, baroreflex sensitivity was significantly associated with adult pulse rate, as previously observed [14,16]. To assess baroreflex sensitivity, we used the spontaneous sequence method, which is currently employed, being an easy and practical method that minimizes risk and circumvents the problems
Mechanisms and implications Spontaneous baroreflex sensitivity reflects the cardiac parasympathetic modulation of heart rate, which may be linked to birth weight through several mechanisms. In general, cardiac baroreceptor reflex can be modulated at different levels, namely at the afferent, central or efferent components of the reflex arch. On the basis of previous findings, an effect of foetal growth on the afferent limb of the reflex arch can be hypothesized: an increased carotid intima-media thickness has been demonstrated in subjects with a lower birth weight in whom increased susceptibility to atherogenesis may come from endothelial dysfunction caused by malnutrition in the uterus [31]. In turn, greater intima media thickness in the carotid bulb, an area with an high density of baroreceptors, may contribute to reduce baroreflex sensitivity by increasing vascular stiffness, so that a higher pressure threshold is required to distend the arterial wall. Indeed, a negative relationship between carotid intima media thickness and baroreflex sensitivity has been recently demonstrated [32]. An increased arterial stiffness has also been attributed to impaired elastin synthesis in arterial walls, caused by haemodynamic changes in the foetal circulation that occur in foetuses showing retarded growth [33]. Moreover, it has been demonstrated that the serum of undernourished rats affects the proliferation of cultured vascular smooth muscle cells [34]. Centrally, neurohormonal changes that influence baroreflex efferent autonomic pathway as well as activation of other neural reflex pathways are potential factors that may be modified in foetal nutrient deprivation [35]. An impaired foetal growth may reduce baroreflex sensitivity by activating on the renineangiotensin system, therefore affecting the central nervous processing of baroreceptor afferent signals or the efferent limb of the reflex arch. This mechanism has been
308 Table 2
G. Leotta et al. Linear regression analysis of baroreflex sensitivity (expressed on a logarithmic scale)
Independent variables
Baroreflex sensitivity Model 1
Intercept Birth weight (kg) Gestational agea Adolescent weight (kg) Adolescent height (cm) Sexual developmentb Adult weight (kg) Adult height (cm) Adolescent weight/adult weight interaction Adolescent systolic blood pressure (mmHg) Adolescent diastolic blood pressure (mmHg) Adolescent pulse rate (beats/min) Adult systolic blood pressure (mmHg) Adult diastolic blood pressure (mmHg) Adult pulse rate (mmHg) Adolescent sport (h/week) Adolescent TV (h/day) Adult sportc Smoking habits (cigarettes/day) Alcohol consumption (g/day) Family history of hypertensiond
Full model 2
b (p)
R
2.57 (<0.0001) 0.16 (0.008)
0.04
Partial R2
b (p) 5.87 0.15 0.0005 0.007 0.007 0.04 0.02 0.001 0.0002 0.0005 0.004 0.005 0.002 0.001 0.01 0.02 0.06 0.04 0.0006 0.001 0.07
(<0.0001) (0.03) (0.99) (0.67) (0.31) (0.53) (0.22) (0.85) (0.51) (0.90) (0.18) (0.18) (0.66) (0.84) (0.002) (0.10) (0.03) (0.57) (0.89) (0.70) (0.27)
0.05 0 0.02 0.008 0.002 0.01 0.03 0.003 0.0001 0.02 0.008 0.001 0.0001 0.12 0.01 0.02 0.003 0.0001 0.0008 0.008
Model 1: unadjusted. Full model: adjusted for gestational age, adolescent weight, adolescent height, sexual development, adult weight, adult height, interaction adolescent weight/adult weight, adolescent blood pressure, adolescent heart rate, adult blood pressure, adult HR, adolescent sport and TV, adult smoking habits, alcohol consumption, sport and hypertensive familiarity. Adjusted R2 for full model ¼ 0.22. a 0, preterm born; 1, term born. b 0, low sexual development; 1, intermediate sexual development; 2, complete sexual development. c 0, high physical activity; 1, low physical activity (see text for explanation). d 0, no; 1, yes (see text for explanation).
hypothesized in a recent experimental study conducted on the adult offspring of Wistar rats: in the animals subjected to protein deprivation during the foetal period, a reduced arterial baroreflex control of heart rate, an increased blood pressure variability and an enhanced expression of brain AT(1) receptors was observed [18]. Similarly, periimplantation global underfeeding has been found to blunt baroreflex control of heart rate during angiotensin II infusion in young adult sheep [19]. In our study, only the baroreflex modulation of the efferent cardiovagal effector mechanism has been evaluated. However, since baroreceptors are also involved in the control of sympathetic nerve traffic, reduced baroreflex sensitivity could explain the increased sympathetic activity recently found in subjects with low birth weight [9,36].
Perspectives This work shows a positive relationship between birth weight and spontaneous baroreflex sensitivity
in young adults. The strength of the association may be more evident in subjects with low birth weight. We cannot compare it to similar studies since, to our knowledge, the effect of foetal growth on baroreflex function in human beings has not been investigated to date. However, our finding is consistent with the results of a recent experimental study performed on Wistar rats, in which arterial baroreflex control of heart rate was reduced in the case of protein deprivation during the foetal period [17]. Similarly, peri-implantation global underfeeding has been found to blunt baroreflex control of heart rate during angiotensin II infusion in young adult sheep [18]. It may be hypothesized that reduced baroreflex sensitivity in low birth weight subjects represents a link between foetal growth and cardiovascular disease since, in epidemiological studies, both low birth weight and baroreflex abnormalities have been associated with an increased cardiovascular morbidity and mortality.
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Further studies will need to unravel the relationship between foetal growth, baroreflex sensitivity and cardiovascular morbidity, and to clarify whether an improvement in foetal nutrition might contribute towards preventing adult disease.
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Acknowledgements This work was supported by a grant (19.700/ 27.001) of Regione Piemonte. We thank Turin General practitioners for their invaluable help in recalling the population studied ten years later.
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