Impaired baroreflex function during pregnancy is associated

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1 Ultrasound Obstet Gynecol 2002; 20: Impaired baroreflex function during pregnancy is associated Blackwell Science, Ltd with stiffening of the carotid artery Z. VISONTAI*, Z. LENARD*, P. STUDINGER*, J. RIGO JR and M. KOLLAI* *Institute of Human Physiology and Clinical Experimental Research and First Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary KEYWORDS: Baroreflex sensitivity, Carotid artery distensibility, Pregnancy, Ultrasound ABSTRACT Objective The baroreflex sensitivity and the distensibility of the carotid artery were measured during normotensive pregnancy to test the hypothesis that changes in baroreflex sensitivity are related to carotid artery stiffening. Design Data were obtained from pregnant subjects during each trimester (T 1 ; n = 23) and postpartum (n = 11). End-diastolic diameter and pulsatile distension of the carotid artery were measured with an ultrasound wall-tracking system, and the distensibility coefficient was calculated. Spontaneous fluctuations in cardiac interval and systolic pressure were used to determine baroreflex sensitivity. Results Both distensibility coefficient and baroreflex sensitivity were reduced from T 1 (5.1 ± 1.6 vs. 3.7 ± /mmhg and 10.1 ± 2.9 vs. 5.7 ± 1.8 ms/mmhg, respectively). Baroreflex sensitivity and carotid distensibility coefficient were linearly related in each subject (r = 0.62 ± 0.12). Augmentation index and return time changes indicated a global increase in arterial distensibility. Conclusions Stiffening of the carotid artery significantly contributes to the impairment of baroreflex sensitivity during pregnancy, and represents a region specific change as global arterial distensibility was found to increase during pregnancy. INTRODUCTION Pregnancy is associated with characteristic changes in hemodynamic function: peripheral resistance falls and plasma volume, stroke volume, heart rate and cardiac output increase, whereas blood pressure either remains unchanged or is slightly reduced 1. This state of a high flow low resistance circulation is paralleled by increased aortic compliance and distensibility, providing optimal coupling between the heart and the vasculature 2 5. Aortic elastic behavior has been studied during normal human pregnancy and in pregnant animals 2 5. However, it is not known whether other segments of the arterial tree behave in a similar manner during pregnancy. Arterial distensibility is not uniform, but is regionally differentiated. Pulse-wave velocity was found to be higher in the ascending aorta and in the iliac artery compared to the thoracic aorta 6. In healthy subjects, the brachial artery was found to be stiffer than the aorta 7. With age and essential hypertension, the carotid artery stiffens to a greater extent than other regions of the arterial tree 8,9. The sensitivity of the arterial baroreflex is known to be reduced during normal pregnancy, but the mechanism of baroreflex impairment is unclear In healthy individuals, the sensitivity of the arterial baroreflex is directly related to the distensibility of the carotid artery 13. With advancing age, and in hypertension, both baroreflex sensitivity and distensibility of the carotid artery are reduced 9,14,15. The reduced baroreflex sensitivity during pregnancy that is associated with increased arterial distensibility therefore appears to be a paradox. In view of the above controversy, we investigated whether, in normal pregnancy, changes in carotid artery distensibility were related to reductions in baroreflex sensitivity. We aimed to collect data that could be used as reference for future studies on arterial elasticity and baroreflex function in hypertensive pregnancy. To this end, we measured carotid artery diameter and its pulsatile distension with an echo-track device; determined baroreflex sensitivity as the slope of the relationship between spontaneous changes in systolic pressure and cardiac cycle interval; and inferred changes in global arterial distensibility from the analysis of the pulsatile carotid distension waveform 16. METHODS Subjects Twenty-three healthy women with singleton pregnancies (eight of whom were primigravidas) of mean age 28 (SD, Correspondence: Dr Mark Kollai, Semmelweis University, Institute of Human Physiology and Clinical Experimental Research, H-1082 Budapest, Ulloi ut 78/a, Hungary ( kollai@elet2.sote.hu) Accepted ORIGINAL PAPER

2 4) years were studied longitudinally, approximately at the end of each trimester (T 1 and T 3, respectively) and, out of these 23 subjects, 11 were also studied between 3 and 6 months postpartum. The subjects were hospitalized at the time of the study, but were healthy and remained normotensive throughout their pregnancies. Hospitalization ensured that the women complied with the required standard conditions (i.e. that they refrained from consuming coffee or alcohol, had the same light meal, and did not perform physical exercise). None of the women was taking medication other than iron or vitamins. All subjects gave their written informed consent to participate in the study, which was approved by the Ethical Committee of the Semmelweis University Budapest, Hungary. Determination of arterial elastic variables The diameter of the right common carotid artery (CA), and changes thereof with arterial pressure pulse, was measured with sonography. The ultrasound device consisted of a vessel wall echo-tracking system (Wall Track System, WTS, Pie Medical, Maastrict, Netherlands) combined with a conventional ultrasound scanner (Scanner 200 Pie Medical, Maastricht, the Netherlands), which has been described in detail elsewhere 17. In brief, the arteries were visualized in twodimensional mode, then the ultrasound system was switched to M-mode and ultrasound was emitted and received along a selected M-line on sight. The WTS is based on a data-acquisition system capable of capturing the received and amplified radio frequency (RF) signals. After completion of data acquisition, the data were transferred to a personal computer. The first line acquired was then graphically presented on a display, allowing manual identification of the anterior and posterior boundaries by placing two markers representing the sample windows for data processing. To extract the change in position of either the anterior or the posterior walls, the approach based on the cross-correlation model for corresponding segments of subsequent RF lines was applied. To ensure that the signals returned by the same structure were always considered, the position of the sample windows was adjusted according to the observed displacements (tracking window). The difference between the displacements of the signals of the anterior and posterior walls yielded the change in diameter as a function of time (i.e. the distension waveform). Systolic and diastolic blood pressure was measured sphygmomanometrically in the right brachial artery and was also monitored noninvasively beat by beat in the right middle finger (Finapres 2300, Ohmeda, Helsinki, Finland). Carotid artery pulse pressure was measured by applanation tonometry with a Millar SPT-301 probe (Millar Instruments Inc., Houston, TX, USA), and the tonometer curve was calibrated by using the internal electric signal and sphygmomanometric measurements 17. The carotid tonometric pressure was used to calculate the distensibility coefficient (DC). Assessment of intima media thickness The method used to assess intima media thickness (IMT) was introduced by Hoeks et al. 18. Visualization of the carotid artery and RF data acquisition was as described above. After RF data acquisition, the first line was displayed on a computer screen, allowing identification of a window of 3 mm covering the posterior lumen wall transition. The power distribution was averaged to reduce over time artifacts due to arterial wall motion. The RF signals were aligned in phase prior to averaging based upon the displacement detected between observations. Subsequently, an edge detection algorithm was applied to the average envelope (amplitude distribution) of the processed RF signals. The intima position was assigned to the point halfway on the first upslope where the spatial derivative of the envelope exceeded a preselected level for the first time. The same procedure was repeated for the next significant upstroke, which is the media adventitia transition. The outer boundary of the adventitia cannot be distinguished. The difference between the intima position and the media adventitia transition was taken as the IMT. Determination of baroreflex sensitivity (BRS) Spontaneously occurring fluctuations in RR interval and systolic blood pressure were used to determine BRS 19. RR intervals were measured from the electrocardiogram and arterial pressure was recorded continuously from the third finger of the right hand using the volume-clamp method by means of a non-invasive blood pressure monitor (Finapres 2300, Ohmeda). This device has been shown to provide good estimates of changes in intra-arterial pressure during baroreflex sensitivity testing 20. During data collection, the servo-reset mechanism of the Finapres was turned off to permit continuous data acquisition. For analysis of a 10-min resting recording period, the computer software selected all sequences of three or more heart beats with concordant increases in systolic pressure and RR interval. Linear regression was applied to each of these sequences and the average regression slope was calculated from those in which the correlation coefficient was higher than The value of the slope was taken as a measure of BRS. Protocol The subjects reported to the laboratory in the early afternoon 2 3 h after a light meal. During the day of the study, they refrained from consuming coffee or alcohol. The subjects were instrumented for electrocardiographic and arterial blood pressure recordings and were rested for 15 min in the left lateral position. This was followed by BRS determination and sonography of the right CA. At least five successful recordings were obtained from the artery. Data analysis The compliance coefficient (CC) was calculated as πd D/ 2 P, and the DC as 2 D/(D P), where D is end-diastolic diameter, D is the change in diameter from end diastole to peak systole and P is pulse pressure. The coefficients of variation for carotid dimensions, compliance and distensibility were < 10% in each of our subjects, which agree well with previously published data 17. Ultrasound in Obstetrics and Gynecology 365

3 Figure 1 Graphic representation of the augmentation index (AIX) and return time (RT). D, distension wave amplitude; A, change from peak distension to the late systolic peak. AIX is defined as ratio of A/ D. RT is defined as the time period from the root of the distension wave to the appearance of the late systolic peak. Carotid distension waveform analysis The analysis of the carotid distension waveform was performed in a way analogous to that of the pulse pressure waveform, as the shape of the two curves are very similar. The carotid pulse waveform is known to manifest an inflection point that divides the waveform into early and late systolic peaks, produced by the forward and the reflected waves. In young, healthy subjects, the early peak, caused by the forward wave, is larger, whereas the reflected peak is of lesser magnitude (Murgo type-c) 16. The ratio of the difference between the two peaks ( A) to the pulse amplitude ( D) is taken as the augmentation index (AIX) (Figure 1). With the type-c waveform, AIX has negative values. The time from the foot of the forward wave to the appearance of the reflected wave is defined as the return time (RT). With increasing arterial distensibility, AIX decreases or attains larger negative values, whereas RT lengthens. Statistical analysis Data are given as mean ± standard deviation (SD) unless stated otherwise. Subjects were studied serially on three or four occasions and one-way repeated measure anova with Figure 2 Changes in carotid artery distensibility coefficient (DC, empty circles) and baroreflex sensitivity (BRS, filled circles) during the three trimesters of pregnancy (T 1, respectively; n = 23, for each trimester) and postpartum (PP, n = 11). Values are mean and standard error of the mean. Tukey s post-hoc test for multiple comparison was used to test for differences among periods. The relationship between carotid wall distensibility and BRS was evaluated by linear regression analysis. Differences were considered significant at P < Statistical analyses were performed using Statistica software package for Windows, release 5.0 (Statsoft, Tulsa, OK, USA). RESULTS Longitudinal changes in cardiovascular variables observed during the three trimesters of pregnancy (T 1, respectively) and postpartum are given in Table 1. Systolic and diastolic pressure did not change significantly through the observation period, whereas heart rate increased. BRS was greatly reduced from T 1 to T 2 and showed a further slight decline from T 2. In the postpartum period, BRS increased and attained values that were not significantly lower than at T 1 (Figure 2). The extent of BRS reduction during pregnancy (> 40%) was comparable to data reported previously 10. Carotid artery dimensions are shown in Table 2. Enddiastolic diameter (D) increased slightly but not significantly from T 1, with a concomitant decrease in pulsatile distension ( D). This was paralleled by increases in the IMT of the carotid artery wall. Because pulse pressure did not change, the above changes in carotid dimensions resulted in Table 1 Clinical characteristics of subjects during the three trimesters of pregnancy (T 1, respectively; n = 23) and postpartum (n = 11) Study point Gestation (weeks) BMI (kg/m 2 ) SP (mmhg) DP (mmhg) HR (bpm) BRS (ms/mmhg) T 1 12 (2) 22.4 (2.0) 120 (9) 78 (8) 82 (7) 10.1 (2.9) T 2 22 (2) 22.7 (2.0) 120 (8) 73 (7) 88 (7)* 5.9 (2.5) T 3 32 (2) 25.2 (2.5) 118 (9) 77 (8) 96 (5) 5.7 (1.8) PP 24 (6) 24.0 (3.0) 120 (8) 75 (10) 83 (5) 8.2 (3.0) Values are means (SD). One-way repeated measures anova was performed, if significant, Tukey s pairwise multiple comparison procedures were performed among periods T 1 and PP. *Statistically different from T 1 at P < 0.05; statistically different from T 1 at P < 0.001; statistically different from PP at P < BMI, body mass index; SP, systolic pressure; DP, diastolic pressure; HR, heart rate; BRS, baroreflex sensitivity; PP, postpartum. 366 Ultrasound in Obstetrics and Gynecology

4 Table 2 Carotid artery dimensions with measures of elasticity and wave reflection during the three trimesters of pregnancy (T 1, respectively; n = 23) and postpartum (n = 11) Study point D (µm) D (µm) IMT (µm) CC (mm 2 /mmhg) DC (10 3 /mmhg) RT (ms) AIX T (527) 601 (158) 451 (28) (0.056) 5.13 (1.64) 126 (19) 0.07 (0.05) T (489) 569 (154) 476 (44) (0.045) 4.07 (1.18)* 155 (21) 0.15 (0.06) T (459) 462 (154)* 493 (43)* (0.037)* 3.70 (0.91) 168 (18) 0.20 (0.07) PP 5941 (656) 548 (133) 484 (53) (0.057) 4.23 (1.08) 129 (13) 0.06 (0.06) Values are means (SD). One-way repeated measures anova was performed, if significant, Tukey s pairwise multiple comparison procedures were performed among periods T 1 and PP. *Statistically different from T 1 at P < 0.05; statistically different from T 1 at P < 0.001; statistically different from PP at P < D, end-diastolic diameter; D, pulsatile distension; IMT, intima media thickness; CC, cross-sectional compliance coefficient; DC, distensibility coefficient; RT, return time for the reflected pulse wave; AIX, augmentation index for the distension waveform; PP, postpartum. Figure 3 Scatter diagram of corresponding baroreflex sensitivity (BRS) and carotid artery distensibility (DC) data collected from the three trimesters of pregnancy (T 1, respectively; n = 23 for each trimester) and from postpartum (PP, n = 11). decreases in carotid compliance and distensibility coefficients (CC and DC, respectively) (Table 2 and Figure 2). A scatter diagram for corresponding BRS and DC values is shown in Figure 3. BRS was regressed against DC in each subject and the correlation coefficients were averaged separately for subjects with three (T 1 and T 3 ) and four (T 1, T 3 and postpartum) measurement points. The analysis indicated significant direct proportionality between BRS and DC in both groups (r = 0.61 ± 0.11 and 0.64 ± 0.13, respectively) and also when data were lumped together (r = 0.62 ± 0.12). By contrast, global arterial distensibility appeared to increase during pregnancy, as inferred from changes in AIX and RT. RT increased significantly from T 1 and AIX attained larger negative values (Table 2). The representative distension waves of Figure 4, recorded from the same individual during pregnancy and postpartum, illustrate the above described changes in carotid dimensions and wave reflection. DISCUSSION Arterial elasticity in normal pregnancy Information on pregnancy related changes in arterial elastic behavior is scarce. Analysis of the diastolic decay of the aortic pressure waveform indicated an increase in global arterial Figure 4 Distension waves recorded from the common carotid artery in the same individual during the three trimesters of pregnancy (T 1, respectively) and postpartum (PP). compliance, to which both conduit and peripheral vessels contributed 3. Pulse wave velocity, measured from the carotid to the femoral artery, was found to be reduced during pregnancy, as a result of increased arterial (mainly aortic) distensibility 4. Using conventional M-mode echocardiography, Hart et al. found the ascending aorta to be larger and more compliant in pregnant women compared to controls 5. In agreement with these observations, we demonstrated in the present work that global arterial distensibility measured through changes in the AIX and RT was increased. When global arterial distensibility increases, pulse wave velocity is reduced and the reflected pulse wave arrives back to the carotid artery later and with a smaller amplitude. Our important finding, that the carotid artery becomes stiffer during pregnancy, is new and is at variance with previous reports. The reason for the discrepancy is not clear, but several factors could be considered. Methodological errors It seems unlikely that carotid diameter and distension were measured with a significant error. Previously, the wall-track ultrasound technique has been widely used in several laboratories, including ours. The accuracy of the method to measure pulsatile distension is less than 10 µm. The reproducibility of determination for vessel diameter, distension and distensibility was tested in our and in other laboratories and was found to be less than 10% 17. Ultrasound in Obstetrics and Gynecology 367

5 Differences in the methods employed The methods employed in earlier studies to assess arterial elasticity were fundamentally different: the analysis of diastolic arterial pressure decay yields information on systemic arterial compliance 3 ; measurement of pulse wave velocity gives an estimate of the average distensibility of an extended arterial segment involved 4 ; and conventional M-mode echocardiography is considered to have low resolution to detect changes in aortic diameter with sufficient accuracy 21. The present study is the first in which the distensibility of an artery was measured locally at a given site and with high accuracy. Differences in the vascular region studied In earlier studies, either global arterial or aortic compliance was measured. This is the first study in which the elastic behavior of the carotid artery was investigated during pregnancy and in the puerperium. It appears that gestational changes in the elastic properties of the carotid artery are different from those of the aorta, and the carotid artery stiffens independently of other arterial beds. Stiffening of the carotid artery during pregnancy The idea of potential vessel wall stiffening during pregnancy is not without support. In pregnant rats, arterial remodeling has been observed with a reduction of vessel wall elastin concentration and a marked increase of smooth muscle 22. This latter finding is in agreement with our observation that the IMT increased during pregnancy. Stiffening of the carotid artery could be also of functional origin. Arterial smooth muscle cells express both estrogen 23 and angiotensin II receptors 24 the former producing vasodilator and latter vasoconstrictor effects. The plasma level of both estrogen and angiotensin II increases 25 during pregnancy and the relative densities of the respective receptors are likely to determine the integrated response of vascular smooth muscle. It is speculated that the relative density of hormone receptors with opposing effects on vascular smooth muscle varies in different segments of the arterial tree, producing contraction in the carotid artery and relaxation in other arteries (such as the aorta). It has been proposed that vascular smooth muscle is arranged in series with the collagen elements and both are in parallel with the elastic lamellae. Contraction of smooth muscle transfers stress to the collagenous elements in the wall and renders the wall stiffer 26. The presumed dominance of angiotensin II over estrogen receptors in the carotid artery smooth muscle could result in stiffening of the vessel wall during pregnancy. This proposed mechanism might have relevance in the pathogenesis of pre-eclamptic hypertension, which is a hypothesis that remains to be tested. Arterial baroreflex function in pregnancy All recent studies agree that baroreflex sensitivity is reduced at T 3 in comparison with data obtained at T 1 or postpartum 10 12, and our present data are in support of these findings. The mechanism of baroreflex impairment is not known, and the attenuation of reflex sensitivity can be introduced at any site along the reflex arch. Recently, we have shown that baroreflex sensitivity was directly related to the distensibility of the carotid arterial wall in young healthy subjects (r = 0.83) 13. This relationship was also demonstrated in this study for first-trimester healthy pregnant women (r = 0.67), but did not reach significance at T 2 and T 3, probably because of the smaller scatter of data due to reduction in both baroreflex sensitivity and carotid wall distensibility values. Our findings also indicate that the contribution of carotid artery stiffening to baroreflex impairment is limited: changes in carotid artery DC accounted only for approximately 40% of variability in BRS, and the increase in BRS from T 3 to postpartum was significant, whereas that in carotid DC was not. Several factors, other than stiffening of barosensory vessel areas, might play a role in the attenuation of BRS during pregnancy. The renin angiotensin system is activated during pregnancy 24 and angiotensin II was shown to attenuate the baroreflex control of heart rate and to produce a reduction in vagal tone centrally 27, an effect that was recently questioned 28,29. The increase in plasma progesterone level may also alter baroreflex sensitivity. A progesterone metabolite, 3α-hydroxydihydroprogesterone was found to attenuate baroreflex sensitivity by modulating the excitability of gamma-aminobutyric acid receptors at central relay sites 12. There are several limitations to this study. First, we did not measure preconception values; therefore, we cannot define a true baseline for the variables measured during pregnancy and postpartum. We might consider the postpartum condition as baseline; however, it is not known whether the measurement values obtained 3 6 months postpartum represented true control values. At 6 weeks postpartum, heart rate high frequency spectral density values (a vagal tone index) were found to be lower than at T 1 10 ; moreover, 9-month postpartum BRS values were shown to be still reduced compared to T Due to this uncertainty, we deliberately avoided the issue of defining a baseline condition in this work, rather, we focused on changes occurring during the three trimesters of pregnancy and the 3 6 months postpartum period. Second, our subjects did not exhibit significant changes in blood pessure during the course of the study, a finding that is at variance with the generally accepted notion that blood pressure is reduced during pregnancy. However, we do not know whether blood pressure changed from control to T 1, as we are unaware of the preconception values, and the pregnancy related fall in arterial pressure usually develops at the beginning of pregnancy. On the other hand, there are a number of studies in the literature that reported no significant changes in blood pressure during pregnancy Third, the distensibility of the carotid artery was measured in the common carotid, and not in the bifurcation where the arterial baroreceptors originate, because the repeatability of diameter measurements in the common carotid is greater than in the carotid sinus. The distensibility of the common carotid and that of the carotid sinus were shown to be closely related, at least in young, normotensive subjects 9. Finally, the method we used to assess BRS is limited in the sense that only the vagal contribution was determined. 368 Ultrasound in Obstetrics and Gynecology

6 In summary, we have confirmed that arterial baroreflex sensitivity is reduced during pregnancy and, as a major new finding, we have shown, that this impairment of baroreflex function is explained, at least partly, by a reduction in carotid artery wall distensibility. Stiffening of the carotid artery represents a region specific change in arterial elasticity, as global arterial distensibility was found to increase during pregnancy, in agreement with earlier reports. ACKNOWLEDGMENTS This work was supported by the Hungarian National Scientific Research Fund Grant OTKA and the Ministry of Welfare Grant ETT-144/2000. The authors acknowledge the skilled technical assistance of B. Mersich and G. Kovacs and the secretarial help of M. Mile. REFERENCES 1 Duvekot JJ, Cheriex EC, Frans PAA, Menheere PPCA, Peeters LLH. Early pregnancy changes in hemodynamics and volume homeostasis are consecutive adjustments triggered by a primary fall in systemic vascular tone. 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