Absence of any significant effects of circadian blood pressure ... - Nature

Journal of Human Hypertension (2000) 14, 813–818  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh

ORIGINAL ARTICLE

Absence of any significant effects of circadian blood pressure variations on carotid artery elastic properties in essential hypertensive subjects C Tsioufis, C Stefanadis, D Antoniadis, I Kallikazaros, P Zambaras, C Pitsavos, E Tsiamis and P Toutouzas Department of Cardiology, University of Athens, Hippokration Hospital, Athens, Greece

We sought in this study to examine the effects of diurnal blood pressure variations upon common carotid artery (CCA) elasticity in selected subjects with uncomplicated moderate essential hypertension. Towards this end, 174 non-smoker subjects with stage I-II essential hypertension and without diabetes mellitus, left ventricular hypertrophy and carotid atherosclerosis, were classified as dippers and non-dippers according to the diurnal variation of ⬎10% between mean daytime and night-time systolic and diastolic blood pressure (BP) in 24-h noninvasive ambulatory BP monitoring. CCA distensibility was derived by a combination of surface ultrasonographic data and simultaneous BP measurements at the brachial artery. The dippers and non-dippers were similar with respect to demographic characteristics. Non-dippers had significantly greater office systolic BP, 24-h systolic BP and ambulatory pulse pressure (PP) and significantly less (daytime–night-time) systolic and diastolic BP fall (by 16 mm Hg and 11 mm Hg respectively, P ⬍ 0.0001) compared to dippers. CCA distens-

ibility was significantly reduced in non-dippers compared to dippers (by 0.89 dyne−1/cm2/10−6, P ⬍ 0.05). Multiple linear regression analysis identified patient age and ambulatory PP as significant predictors of the CCA elasticity index. When patient age, 24-h systolic and diastolic BP were used as covariates in an analysis of covariance, the difference of CCA elasticity between dippers and non-dippers ceased to reach statistical significance. In contrast, when patient age, ambulatory PP, systolic (daytime–night-time) BP fall and diastolic (daytime–night-time) BP fall were used as covariates, the difference of CCA distensibility between dippers and non-dippers continued to be statistically significant. In conclusion, the excessive impairment of CCA elastic properties in non-dippers compared to dippers hypertensive seems to be ascribed to the increased of total 24-h haemodynamic load and not to the circadian pattern of BP. Journal of Human Hypertension (2000) 14, 813–818

Keywords: dippers and non-dippers; carotid artery elastic properties; blood pressure variability

Introduction It is well demonstrated that ambulatory blood pressure (ABP) correlates better with target organ damage than office blood pressure (BP).1,2 Furthermore, some studies have supported that patients with a blunted nocturnal fall in BP, which reflects the potential detrimental effect of a persistent pressure overload, displayed greater end-organ damage.3–5 Hypertension-induced impairment of arterial elasticity plays an important role in the modulation of left ventricular (LV) performance and coronary blood flow and may be directly related to the classic complications of hypertension involving the central nervous system, heart and kidney.6–8 Whether an association exists between the absence of a normal fall of BP at night and the functional status of large

Correspondence: Costas Tsioufis, 4 Athanasiou Diakou Street, 15127 Melissia, Greece. Fax: 0030 1 7701950, or 30 1 7784590 Received 19 January 2000; revised and accepted 24 June 2000

elastic arteries in hypertensive subjects remains to be established. The purpose of this study was to investigate the effect of diurnal fluctuations of BP, measured noninvasively by 24-h monitoring, on common carotid artery (CCA) elastic properties in selected patients with essential hypertension.

Subjects and methods The population in our study consisted of 282 subjects with essential hypertension, (mean age 51 ± 10.3 years) referred to the out-patient hypertension unit. Patients were included if they presented stage I–II (JNC-VI)9 uncomplicated essential hypertension diagnosed during the last 5 years, and who were either never treated with drugs or whose treatment had been discontinued for at least the last 4 weeks prior to inclusion. Presence and severity of hypertension were determined on the basis of office BP measurements obtained during three consecutive visits scheduled 2 weeks apart, by the auscultatory

Diurnal blood pressure changes and carotid artery elasticity C Tsioufis et al

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method with a mercury sphygmomanometer and adapted cuff at the brachial artery, after patients had rested for 15 min in the sitting position. Korotkoff phases I and V were taken as systolic and diastolic BP values, respectively.9 Three consecutive measurements were performed at 5-min intervals and the mean values for systolic and diastolic BP were noted. To confirm essential hypertension, patients were checked for standard biology, plasma renin activity, 24-h urinary sodium and potassium plasma and catecholamine metabolite excretion. The initial workup also included transthoracic echocardiography and carotid artery ultrasonography; subjects with poor-quality acoustic window for examination were excluded from the study, as well as those in whom carotid artery atherosclerotic plaque (defined as a thickening of the wall ⭓50% of the surrounding wall)10 or LV hypertrophy was detected. Additional exclusion criteria included a history of any cardiac disease, diabetes mellitus, familial hypercholesterolaemia or any other clinically significant concurrent medical conditions such as renal, hepatic or gastrointestinal illness. Women receiving long-term treatment with oestrogen replacement therapy were also excluded. Furthermore, all studied patients were non-smokers; being defined as patients who had either never smoked or who had quit smoking for at least 12 months prior to enrolment in the study. Finally, 212 hypertensive patients fulfilling the above criteria were selected for participation in the present study. The study protocol was approved by our institutional ethics committee and all patients gave written informed consent before participating.

Ambulatory BP monitoring ABP was recorded twice with a 1-week interval over a working day (Monday through Friday) using the automatic SpaceLabs units 90202 and 90207 (Redmond, WA, USA). The procedure has been previously described in detail.11 In brief, the cuff was fixed to the non-dominant arm and the device was set to obtain automatic heart rate and BP readings at 15-min intervals during the daytime and at 30-min intervals during the night-time. In keeping with current practice, daytime and night-time were defined using short fixed-clocktime intervals, which ranged from 10.00 am to 8.00 pm and from midnight to 6.00 am respectively.12 Re-examination was performed in five hypertensive patients who complained of sleep disturbance during BP monitoring. According to the criterion of Verdecchia,2 hypertensive patients with a nocturnal reduction in average daytime systolic and diastolic BP of less than 10% were considered as non-dippers. The remaining subjects were classified as dippers. Since the reproducibility of circadian BP variation is limited13 we included in the final analysis 174 subjects who were invariably either dippers or non-dippers in both ABP monitoring evaluation while we excluded the remaining subjects who showed fluctuation between the two. Journal of Human Hypertension

Cardiac and carotid artery ultrasonography The cardiac and CCA ultrasonographic studies were performed by a senior echocardiographer between 8.00 and 9.00 am under controlled room temperature of 20 ± 1°C and constant noise and light intensity. Patients were allowed to rest at the supine position for 15–20 min prior to the examination. A Hewlett-Packard Sonos 2500 ultrasound imager equipped with a 2.25–5 MHz and a 7.5 MHz transducer was employed in all cases. Images were recorded on super VHS videotapes and measurements were subsequently performed off-line by two independent operators, who were blinded with respect to the patients’ demographics and BP status. At the parasternal long-axis view, two-dimensional guided M-mode echocardiography was performed and LV end-systolic and end-diastolic dimension as well as intraventricular septum and posterior wall thickness were measured as the mean from five consecutive cardiac cycles, according to the recommendations of the American Society of Echocardiography.14,15 Subsequently, we calculated the relative wall thickness, the LV mass by using the Penn convention and LV mass index (LVMI) by dividing LV mass by the body surface area. Long axis B-Mode images of the right CCA were obtained in three projections (anterior, posterior and lateral) in order to acquire good-quality visualisation of the near and far vessel wall. The measurement site was set at 1.5 cm central to the carotid bifurcation. The CCA systolic diameter and diastolic diameter were determined in frames corresponding to the largest and smallest diameters in the circle respectively. Both CCA systolic and diastolic diameters were measured as the distance between the intima-lumen interface of the near and far walls.10,16–19 Values were measured over five consecutive cardiac cycles and averaged. For the calculation of CCA elasticity, pulse rate and BP were measured at the brachial artery with the use of an automatic oscillometric device (Dinamap XL, Johnson & Johnson Inc) simultaneously with the performance of CCA ultrasonographic studies. BP values for measurements were obtained after the achievement of a steady haemodynamic state, manifested by pulse rate variation of less than five beats per minute and systolic and diastolic BP variation of less than 5 mm Hg over two consecutive measurements. PP was calculated as the difference between systolic and diastolic BP values. The CCA measurements were combined with the simultaneous oscillometric BP readings to calculate the CCA distensibility by the following formula: Carotid artery distensibility =2× [pulsatile changes of CCA diameter]/[CCA diastolic diameter × PP] [dyne−1/cm2/10−6]). Repeatability of arterial measurements Repeatability of the ultrasographic method to calculate CCA diameters was investigated in 12 patients through calculation of the repeatability coefficient (RC), as defined by the British Standard Institution and according to the formula RC2 = (⌺Di2)/N where


N is the sample size and Di the relative difference between each pair of measurements.20 The 95% confidence interval of the expected difference was calculated as ±1.96 RC. The RC values for the intraobserver repeatability (comparison of two determinations obtained in 2 days intervals by the same observer) concerning CCA systolic and diastolic diameter and its pulsatile changes were 0.031, 0.028 and 0.0021 cm, respectively. These values were small compared to the mean values of CCA systolic and diastolic dimension and its pulsatile changes in the sample. Statistical analysis Data is expressed as mean ± s.d. Significant differences between dippers and non-dippers were determined by using the independent sample t-test. Stepwise multiple linear regression analysis, with inclusion criteria at the 0.01 level and exclusion criteria at the 0.05 level, was used to evaluate the relation of demographic and haemodynamic variables with CCA distensibility. An analysis of covariance (ANCOVA) was performed in order to detect significant differences of CCA elasticity between dippers and non-dippers after the adjustment of a number of covariates, which were linear, related to the dependent variable. All tests were considered to be significant at the level of P ⬍ 0.05.

Results The clinical characteristics and office BP data of the entire study population are presented in Table 1. Based on our definition, 102 hypertensive patients were classified as dippers and 72 as non-dippers. The dippers and non-dippers were similar with respect to age, gender and body surface area. Office systolic and diastolic BP were significantly increased in non-dippers compared to dippers (by 9 and 7 mm Hg, respectively, P ⬍ 0.05). The ABP monitoring data are presented in Table 2. Non-dippers had significantly greater 24-h SBP (by 9 mm Hg, P ⬍ 0.05), night-time systolic and diastolic BP (by 19 and 10 mm Hg respectively, P ⬍ 0.001) and significant less (daytime–night-time) systolic BP fall (by 16.2 mm Hg, P ⬍ 0.0001) and (daytime–night-time) diastolic BP fall (by 11.7 mm Hg, P ⬍ 0.0001) compared to dippers. Furthermore, non-dippers were characterised by a significantly greater ambulatory pulse pressure (PP) (by 5.9

mm Hg, P ⬍ 0.001) than the dippers. In addition, the 24-h systolic BP load was significantly increased in non-dippers compared to dippers (by 20%, P ⬍ 0.05). However, there were no significant differences in any heart rate parameter between dippers and non-dippers as the decline in heart rate during sleep was not significantly different among the two groups. Regarding the echocardiographic measurements, non-dippers had greater intraventricular septum (1.11 ± 0.11 vs 1.05 ± 0.01 cm, P ⬍ 0.05), posterior wall (1.09 ± 0.01 vs 1.03 ± 0.01 cm, P ⬍ 0.05) and relative wall thickness (0.50 ± 0.04 vs 0.46 ± 0.04, P ⬍ 0.005) compared to dippers. In contrast, the two groups did not differ as far as LVMI is concerned (96.6 ± 22 vs 90.6 ± 16 gr/m2, P: NS). The CCA measurements and the oscillometric BP data are presented in Table 3. Oscillometric PP was greater in non-dippers compared to dippers (by 4 mm Hg), but this difference was not statistically significant. CCA systolic and diastolic dimension did not differ between dippers and non-dippers; the pulsatile changes of CCA diameter were greater in dippers compared to the non-dippers (by 0.008 cm) but this increase was not statistically significant. The distensibility of CCA was significantly impaired in non-dippers compared to dippers by 0.89 dyne−1/cm2/10−6 (P ⬍ 0.05). Forward multiple linear regression analysis performed on demographic characteristics, ABP data and LV echocardiographic measurements identified patient’s age and ambulatory PP as significant predictors of the CCA distensibility, in the entire study population (Table 4). Similarly, we applied another regression analysis model in which age, 24-h systolic BP, 24-h diastolic BP, systolic (daytime–nighttime) BP fall and diastolic (daytime–night-time) BP fall were used as independent variables and CCA elasticity index as dependent variable. This analysis revealed that age and 24-h systolic BP were significantly associated with CCA distensibility (R2 = 0.37, P ⬍ 0.0001). When the patient’s age, 24-h systolic BP and 24-h diastolic BP were used as covariates in an analysis of covariance (ANCOVA), the difference of CCA distensibility, between dippers and non-dippers ceased to reach statistical significance (P = 0.206). In contrast, when the patient’s age, ambulatory PP, systolic (daytime–night-time) BP fall and diastolic (daytime–night-time) BP fall, were used as covariates in an analysis of covariance, the differ-

815

Table 1 Clinical characteristics and BP data of the entire study population Hypertensive subjects

Age Men/women Body surface area (m2/Kg) Office systolic BP (mm Hg) Office diastolic BP (mm Hg)

Entire study population (n = 174)

Dippers

non-Dippers

(n = 102)

(n = 72)

54.2 ± 10 100/74 1.83 ± 0.18 154 ± 18 97 ± 12

53.3 ± 9.5 61/41 1.84 ± 0.2 150 ± 18 94 ± 8

55.9 ± 11 39/33 1.81 ± 0.2 159 ± 19 101 ± 15

P

NS NS NS 0.02 0.04

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Table 2 Ambulatory BP monitoring data of the entire study population Parameters

Hypertensive subjects Entire study population (n = 174)

24-h systolic BP (mm Hg) 24-h diastolic BP (mm Hg) 24-h ambulatory PP (mm Hg) Daytime systolic BP (mm Hg) Daytime diastolic BP (mm Hg) Night-time systolic BP (mm Hg) Night-time diastolic BP (mm Hg) (Daytime–night-time) systolic BP fall (mm Hg) (Daytime–night-time) diastolic BP fall (mm Hg) 24-h systolic BP load (%) 24-h diastolic BP load (%) 24-h heart rate (bpm)

137 85 52 139 88 127 76 11

± ± ± ± ± ± ± ±

13 11 7 12 11 15 11 11

Dippers

Non-dippers

(n = 102)

(n = 72)

132 84 48.5 137 89 117 71 20

± ± ± ± ± ± ± ±

9 5 6 9 5 8 7 7

141 ± 14 86 ± 13 54.4 ± 7 141 ± 14 87 ± 13 136 ± 14 81 ± 12 4±7

P

0.006 NS 0.001 NS NS 0.0001 0.0001 0.0001

12 ± 8

18 ± 7

6±5

0.0001

38 ± 25 35 ± 24 76 ± 12

29 ± 18 34 ± 19 77 ± 14

49 ± 30 39 ± 30 76 ± 13

0.002 NS NS

Dippers

Non-dippers

P

(n = 102)

(n = 72)

Table 3 Carotid artery measurements and oscillometric BP data of the entire study population Parameters

Entire study population (n = 174)

Oscilometric pulse pressure (mm Hg) Carotid systolic diameter (cm) Carotid diastolic diameter (cm) Pulsatile changes of carotid diameter (cm) Carotid distensibility (dyne−1/cm2/10−6)

56.8 0.68 0.64 0.037 2.27

± ± ± ± ±

12 0.08 0.08 0.01 1.5

Table 4 Multiple regression analysis in the entire study population with CCA elasticity index as dependent variables and six independent variables Variables Age Ambulatory pulse pressure Constant

B

T

P

−0.0050 −0.0078

−3.244 −3.533 7.332

0.0019 0.0008 0.0001

The variables daytime–night-time systolic and diastolic BP fall as well as LVMI and RWT did not enter into the equation according to the selection criteria (probability for entry ⬍0.05; probability of removal ⬎0.01).

ence of CCA distensibility persist to be statistically significant (P ⬍ 0.05).

Discussion In the present study we evaluated non-invasively the relationship between the elastic properties of a large artery and the circadian changes of BP in a group of patients with mild to moderate essential hypertension. Our most important finding was that the excessive impairment of CCA mechanics in nondippers hypertensive in comparison to dippers hypertensive seems to be ascribed to the increased of total 24-h haemodynamic load and not to the circadian pattern of BP. A blunted nocturnal fall in BP predicts future cardiovascular events in white women with essential Journal of Human Hypertension

55 0.66 0.62 0.041 2.73

± ± ± ± ±

13 0.06 0.07 0.02 1.8

59 0.69 0.66 0.033 1.84

± ± ± ± ±

11 0.09 0.09 0.01 0.9

NS NS NS NS 0.01

hypertension, but not in men.2 Accordingly, nondippers have been proposed as one subgroup associated with increased frequency of damage to target organs like brain, heart and kidney.21 Possible additional associations between circadian BP changes and functional alterations of other cardiovascular system parts in hypertensive patients have not been well addressed. To investigate this issue further, we focused our attention to the relation between mechanical behaviour of large elastic type arteries and BP variations in the entire 24-h period in subjects with mild to moderate uncomplicated essential hypertension. It is well established that the buffering function of the large elastic arteries is diminished in hypertensive patients;6–8,22 Whatever the underlying causes, the loss of elasticity of large arteries has been recognised to offset the LV-arterial functional coupling over the entire cardiac cycle, to increase the pulsatile component of the LV afterload and to compromise coronary flow thereby contributing to the deleterious effects of hypertension on LV function.6,7,23 However, there are conflicting data regarding the effects of non-dipper status on vascular status. Brien et al4 reported a more frequent history of stroke in non-dippers than in dippers, and Shimada et al24 showed that in elderly essential hypertensive patients, the lack of a nocturnal fall in BP is associated with silent cerebrovascular damage as identified by nuclear magnetic resonance. In a previous study, Roman et al25 did not report any sig-


nificant differences between dippers and non-dippers in both CCA diameter and CCA strain. In our study, in untreated patients with uncomplicated hypertension diagnosed less than 5 years before the study, we found that CCA diameter did not differ in dippers compared to non-dippers but the latter group exhibited impaired elasticity. This disagreement may be explained by the different methodology employed for evaluating CCA function and the different inclusion criteria of the study population regarding the duration of previous antihypertensive treatment, the stage and the duration of hypertension. The latter may be weighted against the findings of Ferrara et al26 who suggested that the unfavourable consequences of non-dipper status might be blunted by the duration of hypertension, as there is no difference between dippers and non-dippers in the patients with long-standing elevated BP levels. In our population, the difference in the CCA elasticity between the two hypertensive subgroups could not be explained only by the degree of nocturnal BP fall, since non-dippers had increased both office systolic and diastolic BP and 24-h systolic BP. Furthermore, ambulatory PP was significantly increased in non-dippers compared to dippers. A high PP may reflect already diseased arterial walls with several adverse cardiac implications of potential prognostic value.8,27 Franklin et al28 have reported that the pulsatile components of the BP are the most sensitive risk markers for the diagnosis of carotid stenosis, and baseline data from European Lacidipine Study of Atheroclerosis29 demonstrated that ambulatory PP plays a major role in influencing intima-media thickness. In concordance with the above, we found that the haemodynamic determinants of CCA elasticity were the 24-h systolic BP and the ambulatory PP while the daytime– night-time systolic and diastolic BP fall did not relate significantly with CCA elasticity. Also, the contribution of 24-h systolic BP on the impairment of CCA elasticity in non-dipper subjects was confirmed by analysis of variance. Consequently, the reduction of CCA distensibility in non-dippers seem to be the result of a higher average 24-h BP and ambulatory PP rather than a lack of marked circadian BP rhythm. Although some previous studies have suggested that hypertensive individuals with a non-dipping nocturnal profile may have a worse prognosis than the majority of hypertensive and normotensive subjects who do show a fall in BP at night, it is unclear whether the reduced day–night BP difference is the cause or the consequence of the increased degree of hypertensive target organ damage.30 This question is still open and remains to be further established by other studies properly designed. The mechanisms proposed to be accounted for the further impairment of CCA elasticity in the non-dippers may be the deterioratory effect of the more increased distending pressure per se on the arterial wall which responds as a two-phase material, the more increased smooth muscle tone secondary to endothelial dysfunction as well as the more decreased flow through the vasa vasorum network in this setting compared to dippers hypertensive subjects.22 Furthermore, Pierdomenico et al17 sug-

gested that the progression of vascular disease may be differently affected in the two sexes by a different circadian BP profile. In our study, LVMI was within normal values and did not differ between non-dippers and dippers. This finding is in contrast with some3 but not all31 reports suggesting that subjects with less diurnal BP fall have greater LV mass. This controversy is possibly due to the usage of different definitions for dippers and non-dippers and/or daytime and night-time periods as well as of different inclusion criteria in these studies.4,21 On the other hand, our finding that non-dippers exhibited significantly increased relative wall thickness is in compliance with the hypothesis that geometric and functional changes in the CCA accompanies geometric changes in the left ventricle.32

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Limitations In the present study CCA elasticity was determined by PP obtained at the site of brachial artery. Given that amplification of PP from central arteries to a more distal one is a well-known phenomenon attributable to pulse wave reflection, the difference between CCA BP and brachial artery BP may affect the accuracy of CCA distensibility.7,22,32 However, the PP estimated non-invasively at the brachial artery is well correlated with that measured directly from the aorta and has been extensively used for determination of the aortic and CCA elastic properties.32 Although the video imaging analysis used for estimation of CCA dimensions has much less reproducibility compared to the echo-tracking method,34 our method has been used previously17,18 and is favoured in clinical practice due to its good repeatability in our arterial measurements. A wide range of definitions is used to distinguish dippers from non-dippers; we choose to classify subjects as dippers or non-dippers based on whether the reduction in both systolic and diastolic BP was above or below an arbitrary value of 10% according to the criterion of Verdecchia, although the prognostic significance of a new index such as night-to-day ratio for systolic and diastolic BP seems to be a convenient way to define non-dipper.35 Furthermore, 41% of our subjects were non-dippers. Although this incidence seems to be high, it is in concordance with previous studies in hypertensive subjects with similar clinical characteristics.25 In addition, since Mochizuki13 reported that there is a risk of false-positive or false-negative results when 24-h recordings are used to identify dippers and non-dippers, we classified our patients by using repeated ABP recording. Our findings that about 82% of the studied subjects remained classified as dippers or non-dippers in both sessions are in agreement with a previous study and suggests that the reproducibility of the dipping status may be acceptable when narrow fixed clock intervals are used for the definition of daytime and night-time period.36

Conclusion The hypertension-induced reduction of CCA elasticity in non-dippers compared to dippers seems to Journal of Human Hypertension


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be caused by a higher average 24-h BP and ambulatory PP rather than a lack of marked circadian BP rhythm.

19

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