Increased Pulse Pressure Is Associated with Reduced Baroreflex Sensitivity

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Journal of Human Hypertension (2004) 18, 247–252 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Increased pulse pressure is associated with reduced baroreflex sensitivity

R Virtanen1, A Jula2, H Huikuri3, T Kuusela4, H Helenius5, A Ylitalo6, L-M Voipio-Pulkki1,7, H Kauma3,8, YA Kesa¨niemi3,8 and J Airaksinen1 1Department of Medicine, University of Turku, Turku, Finland; 2Research Department of the Social Insurance Institution, Turku, Finland; 3Department of Medicine, University of Oulu, Oulu, Finland; 4Department of Physics, University of Turku, Turku, Finland; 5Department of Biostatistics, University of Turku, Turku, Finland; 6Division of Cardiology, Satakunta Central Hospital, Pori, Finland; 7Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; 8Biocenter Oulu, University of Oulu, Oulu, Finland

Although pulse pressure (PP), heart rate variability significant when 24-h ambulatory diastolic blood pres- (HRV) and baroreflex sensitivity (BRS) have been shown sure, body mass index, smoking and alcohol intake were to predict cardiovascular events and mortality in various added as covariates in the multivariate analysis. In- populations, their relationships have not been clarified. creased ambulatory PP was also associated with We examined these associations in two separate increased beat-to-beat systolic arterial pressure varia- population-based samples of healthy middle-aged sub- bility. Associations between ambulatory PP and HRV jects. In population 1, data were obtained from 149 were not significant after controlling for age and gender. subjects (71 men and 78 women) aged 35–64 (mean 47.7) Our results suggest that elevated PP does not affect years, and in population 2, from 214 subjects (88 men overall HRV, but it interferes with baroreflex-mediated and 126 women) aged 40–62 (mean 50.5) years. In- control of the heart rate. This association may be due to creased 24-h ambulatory PP was related to decreased a common denominator, such as arterial stiffness, for cross-spectral BRS independent of age and gender PP and BRS. (b ¼À0.28, Po0.001 for population 1; b ¼À0.22, Journal of Human Hypertension (2004) 18, 247–252. P ¼ 0.003 for population 2). This association remained doi:10.1038/sj.jhh.1001661

Keywords: blood pressure; heart rate; autonomic nervous system; baroreflex; population

Introduction be caused by increased sympathetic nervous activity. PP rises with age probably mainly due to Elevated pulse pressure (PP) is a predictor of increased stiffness of the aorta and its major cardiovascular events and mortality in unselected branches.17,18 Arterial stiffening and increased sym- populations1,2 and in patients with hypertension3–6 7 pathetic activity may not only modify PP by or left ventricular dysfunction. Correspondingly, reducing compliance and increasing pulse wave decreased heart rate variability (HRV)8,9 and barore- 8 velocity, but they may also interfere with baroreflex heart rate control are strong predictors of ceptor-mediated vagal control of the heart. cardiovascular events and mortality in different The purpose of this study was to evaluate whether populations. Hypertension is known to decrease 10–12 13,14 PP is associated with cardiac autonomic nervous HRV and baroreflex control of the heart rate, regulation as assessed with spectral analyses of and there are speculations that abnormalities in HRV, systolic arterial pressure (SAP) variability and autonomic function may sometimes precede or give 15 baroreflex sensitivity (BRS). Two middle-aged rise to hypertension. However, only a little is healthy populations were studied in order to known of the potential interactions between PP and provide data, which can be used to generalize the various measures of autonomic nervous function. possible associations more reliably provided that the Among the young, elevated PP has been connected findings are parallel in both populations. with increased stroke volume,16 which in turn may

Correspondence: Dr R Virtanen, Department of Medicine, Turku Materials and methods University Central Hospital, Kiinamyllynkatu 4–8, FIN-20520 Turku, Finland. Subjects E-mail: [email protected] Received 16 June 2003; revised 8 October 2003; accepted 8 Population 1 comprised of an age- and gender- October 2003 stratified random sample of 270 subjects, aged 35–64 Pulse pressure and baroreflex R Virtanen et al 248 years, drawn from the national population register abilities providing that the coefficient of coherence of inhabitants residing in the vicinity of Turku in between variabilities was 40.5 and the phase angle southwestern Finland. Population 2 consisted of an was negative. In population 1, cross-spectral BRS age- and gender-stratified random sample of 300 was calculated from the LF band, whereas in men and 300 women, aged 40–59 years, selected population 2, MF and HF bands were used. Spectral from the register of the Social Insurance Institution analyses were performed with CPRS (CardioPul- of the inhabitants of Oulu in northern Finland for monary Research Software, Absolute Aliens Ay, the Oulu Project Elucidating Risk of Atherosclerosis Turku, Finland) and in population 2 additionally (OPERA), an epidemiological study of cardiovascu- with CAFTS (CAFTS, Medikro Oy, Finland) soft- lar risk factors.19 Subjects with diabetes mellitus, wares. coronary artery disease, congestive heart failure, previous cerebrovascular events, claudication, hae- modynamically significant valvular disease, signifi- Pulse pressure measurements cant anaemia, chronic alcoholism and subjects using confounding medication (antihypertensives, other PP was defined in both populations as the mean cardiovascular agents, b-blocker eye drops, teophyl- difference of all corresponding ambulatory 24-h systolic and diastolic blood pressure readings. In lamine, b2-sympathomimetics, antidepressants, neu- roleptics or antineoplastic medication) were population 1, ambulatory blood pressure was re- corded with an auscultatory device (Suntech, excluded. After a further exclusion of subjects with 20 inadequate spectral or ambulatory blood pressure Accutracker II), whereas in population 2, Space- recordings, 149 (78 women and 71 men) and 214 Labs 90207 oscillometric unit (SpaceLabs Inc., Red- (126 women and 88 men) subjects in the respective mond, Washington, USA) was used. populations were eligible for the final analyses. The design of the studies was approved by the ethical committees of the respective institutions, and all Statistical analyses subjects gave their informed consent. The summary statistics are given as mean 7 s.d. Gender differences were tested with two samples Student’s t-test for equality of means. Associations Heart rate variability between 24-h ambulatory PP, HRV, beat-to-beat SAP In population 1, HRV was calculated from a 5-min variability, BRS and the other variables were studied supine ECG-recording obtained during controlled with Pearson’s correlation coefficients and linear breathing (0.25 Hz). In population 2, HRV was regression analyses. To find out independent corre- analysed from a 45-min recording with an ambula- lates of BRS and beat-to-beat SAP variability, multi- tory ECG recorder (Dynacord Holter Recorder, variate regression analyses were carried out using Model 420, DM Scientific, Irvine, CA, USA). Ectopic the statistically significant (Po0.05) correlates. The beats, artefacts and arrhythmias were excluded. A effects of age and gender were controlled by forcing fast Fourier transform in population 1 and an them within regression models. Smoking was autoregressive model in population 211 were used analysed as a dichotomous (yes/no) variable. Alco- to assess HRV. For both populations, the standard hol intake was analysed by using four drinking deviation of the normal-to-normal interval (SDNN), categories (no use and three categories according to total power, high-frequency (HF) power (0.15– the tertiles for alcohol intake of men and women). 0.4 Hz), low-frequency (LF) power (0.04–0.15 Hz) Statistical analyses were performed with SPSS 10.0 and very-low-frequency (VLF) power (o0.04 Hz) software (SPSS Inc., Chicago, IL, USA). Po0.05 were computed. Normalized LF and HF powers were considered to be statistically significant. and the ratio of LF to HF were also calculated. Before statistical analyses, the skewed distributions of the measures of HRV, SAP variability and BRS were transformed logarithmically. Regression ana- Systolic arterial pressure variability and baroreflex lyses were carried out with standardized variables sensitivity for comparability of the regression coefficients of different variables. In population 1, the same time series and frequency bands were used for the assessment of SAP variability and cross-spectral BRS as for the assess- Results ment of HRV. In population 2, separate stationary segments without ectopic beats of about 5 min were Ambulatory blood pressure and lifestyle character- used to compute fast Fourier-based total power, LF istics of men and women of the study populations power (0.04–0.06 Hz), mid-frequency (MF) power are presented in Table 1. Women had lower 24-h (0.07–0.14 Hz) and HF power (0.15–0.40 Hz). In both systolic and diastolic blood pressures than men in populations, BRS was analysed by the cross-spectral both populations, but a significant PP difference analysis between R–R interval and photoplethysmo- between men and women was observed only in graphic (Finapres, Ohmeda Inc., USA) SAP vari- population 1. As compared with men, women had a

Journal of Human Hypertension Pulse pressure and baroreflex R Virtanen et al 249 Table 1 Characteristics of men and women in study populations

Population 1 Population 2

Men (n=71) Women (n=78) Men (n=88) Women (n=126)

Age (years) 47.3 7 7.8 48.0 7 7.9 50.1 7 5.9 50.8 7 6.0 Ambulatory systolic BP (mmHg) 124.1 7 14.1 117.2 7 11.9** 128.9 7 13.0 123.8 7 11.9** Ambulatory diastolic BP (mmHg) 75.5 7 8.4 71.3 7 7.3** 80.7 7 7.4 76.4 7 8.0*** Ambulatory pulse pressure (mmHg) 48.6 7 8.4 46.0 7 7.5* 48.2 7 8.4 47.4 7 7.6 Body mass index (kg/m2) 26.4 7 4.0 25.6 7 4.0 26.0 7 3.2 25.8 7 4.1 Obesitya (%) 19.7 14.1 12.5 12.7 Smoking (%) 35.2 24.4 37.5 25.4 Alcohol intake (g/week) 110 7 116 42 7 52*** 83 7 94 24 7 36***

Values are mean 7 s.d. BP=blood pressure. *Po0.05, **Po0.01, ***Po0.001 for the difference between men and women. aBody mass index >30 kg/m2.

Table 2 HRV in study populations

Population 1 Population 2

Men (n=71) Women (n=78) Men (n=88) Women (n=126)

SDNN (ms) 37 7 2377 2587 2587 2 Total power of HRV (ms)2 1420 7 174 1306 7 154 2215 7 160 2301 7 120 VLF power of HRV (ms)2 644 7 112 583 7 95 1221 7 89 1266 7 67 LF power of HRV (ms)2 400 7 53 261 7 33** 517 7 37 528 7 35 HF power of HRV (ms)2 357 7 74 441 7 63 210 7 25 273 7 18** Normalized LF power of HRV (%) 58.0 7 2.2 43.4 7 2.1*** 71.4 7 1.1 65.5 7 0.9*** Normalized HF power of HRV (%) 42.0 7 2.2 56.6 7 2.1*** 28.6 7 1.1 34.5 7 0.9*** LF/HF ratio 1.9 7 0.2 1.1 7 0.1*** 3.0 7 0.2 2.2 7 0.1***

BRS, baroreflex sensitivity; HF, high frequency; HRV, heart rate variability; LF, low frequency; SDNN, standard deviation of normal-to-normal interval; VLF, very low frequency. Values are mean 7 s.e.m. *Po0.05, **Po0.01, ***Po0.001 for the difference between men and women.

Table 3 Beat-to-beat SAP variability and cross-spectral BRS in study populations

Population 1 Population 2

Men (n=71) Women (n=78) Men (n=88) Women (n=126)

Total power of SAP (mmHg)2 37.6 7 4.6 33.8 7 3.1 34.6 7 4.1 40.5 7 2.7* VLF power of SAP (mmHg)2 25.4 7 3.7 21.3 7 2.4 FF LF power of SAP (mmHg)2 9.1 7 1.0 9.6 7 1.1 8.5 7 1.0 10.1 7 0.7 MF power of SAP (mmHg)2 FF5.2 7 0.5 6.7 7 0.5* HF power of SAP (mmHg)2 3.0 7 0.4 2.9 7 0.2 5.3 7 0.4 6.4 7 0.6 BRSa (ms/mmHg) 8.3 7 0.6 7.3 7 0.7** 7.2 7 0.6 7.7 7 0.4

BRS, baroreflex sensitivity; HF, high frequency (0.15–0.40 Hz); LF, low frequency (0.04–0.15 Hz, population 1; 0.04–0.06 Hz, population 2); MF, medium frequency (0.07–0.14 Hz); SAP, systolic arterial pressure; VLF, very low frequency (o0.04 Hz). Values are mean 7 s.e.m. *Po0.05, **Po0.01 for the difference between men and women. aBRS calculated for 67 men and 75 women in population 1, and for 80 men and 117 women in population 2.

consistently lower normalized LF power of HRV, a HRV were not significant after controlling for age higher normalized HF power of HRV and a lower LF and gender. Normalized LF and HF powers and the to HF ratio (Table 2). Women had a lower BRS than LF to HF ratio were not related to PP, as were not the men in population 1, whereas no gender difference HRV changes induced by tilting, either (data not in BRS was observed in population 2 (Table 3). shown). PP correlated inversely with the HF power of HRV In both populations, PP correlated inversely with in population 1 (r ¼À0.18, P ¼ 0.025), and with the BRS (r ¼À0.33, Po0.001, population 1; r ¼À0.29, LF power of HRV in population 2 (r ¼À0.14, Po0.001, population 2), and according to multi- P ¼ 0.039). However, correlations between PP and variate regression analyses, independent of age

Journal of Human Hypertension Pulse pressure and baroreflex R Virtanen et al 250 Table 4 Pulse pressure as a determinant of BRS

Population 1 Population 2

b CI P b CI P

Age (years) À0.28 À0.43 to À0.13 o0.001 À0.23 À0.38 to À0.09 0.002 Gender (female vs male) À0.25 À0.43 to À0.08 0.005 0.03 À0.13 to +0.18 0.746 BMI (kg/m2) À0.20 À0.36 to À0.04 0.015 F Ambulatory pulse pressure (mmHg) À0.20 À0.37 to À0.04 0.018 À0.16 À0.30 to À0.01 0.033 Ambulatory diastolic BP (mmHg) F À0.23 À0.37 to À0.09 0.002

Population 1: Model Po0.001, R2=0.27, n=149 Population 2: Model Po0.001, R2=0.16, n=214

BMI, body mass index; BP, blood pressure; BRS, baroreflex sensitivity. b, regression coefficient corresponding standardized variable (except gender); CI, 95% confidence interval for the regression coefficient; P, significance of the variable in the model; R2=R square. Dependent variable in the analysis was natural logarithmic-corrected BRS. Age and gender were forced in the model. Ambulatory diastolic and pulse pressures, body mass index, alcohol intake and smoking were tested in a stepwise manner.

and gender (standardized regression coefficient, ated BRS and increased PP. A wealth of published b ¼À0.28, Po0.001, population 1; b ¼À0.22, evidence has shown abnormal BRS and HRV in P ¼ 0.003, population 2). In multivariate analyses hypertension,10,11,14,21,22 and BRS has been altered with age, gender, 24-h ambulatory diastolic blood even in borderline hypertensives.13,23 Increased SAP pressure, body mass index, alcohol intake and variability in lower frequencies has been linked to smoking, increased 24-h ambulatory PP was still an increased sympathetic modulation.24 In hyperten- independent determinant of decreased BRS (Table 4). sive subjects, an inverse relationship has been Elevated 24-h PP was related to increased beat-to- reported between BRS and plasma catecholamine beat SAP variability. In multivariate analyses with levels.25 However, in systo-diastolic and systolic explanatory variables corresponding to those shown hypertension, baroreceptor modulation of sympa- in Table 4, higher 24-h ambulatory PP was asso- thetic nerve traffic is still present despite impaired ciated in population 1 with higher total, VLF, LF baroreflex control of the heart rate and increased (b ¼ 0.40, 0.37, 0.31, respectively, Po0.001 for all) muscle sympathetic nerve activity.26,27 Increased and HF (b ¼ 0.28, P ¼ 0.001) powers of SAP varia- sympathetic modulation hardly explains our find- bility, and in population 2, with higher total, LF and ings of reduced BRS and increased SAP variability MF powers of SAP variability (b ¼ 0.16, 0.15 and in relation to increased PP, since the heart rate and 0.16, respectively, Po0.05 for all). HRV did not indicate varying sympathetic tone in relation to PP levels. Increased arterial stiffness and decreased arterial Discussion distensibility are the most probable common de- nominators between increased PP, increased SAP We demonstrated in two separate population-based variability and impaired BRS. PP rises and BRS samples of middle-aged men and women that decreases with ageing, and impaired arterial elasti- increased 24-h ambulatory PP is associated with city may contribute to both these changes.17,28 Even decreased BRS and increased beat-to-beat SAP in young healthy subjects, decreased BRS is asso- variability, independent of age, gender, diastolic ciated with decreased carotid artery distensibility.29 blood pressure, body mass index, smoking and Arterial distensibility is decreased in borderline as alcohol intake. The overall heart rate fluctuations well as in established essential hypertension.30 are determined by multiple factors, which are still Various metabolic and lifestyle factors affect arterial not entirely known. Afferent nerve stimuli derived properties and BRS. For example, exercise train- from blood pressure fluctuations are only some of ing,31 diabetes,32,33 consumption of n-3 fatty acids34 these determinants. In our study, PP had no and salt intake35 have been shown to modify arterial independent association with any of the HRV compliance. Atherosclerosis at such is associated indices, suggesting that PP only affects baroreflex- with decreased aortic distensibility.36–38 Experimen- mediated heart rate fluctuations and does not have tal research has demonstrated that less distensible any significant effect on the general cardiac auto- aortas of atherosclerotic rabbits have less-sensitive nomic control. However, as HRV decreases and PP baroreceptors. Stiffness of the aorta has a splinting increases with increasing age, controlling for age action, which protects baroreceptors from the may theoretically lead to an underestimation of the stretch normally caused by a rise in arterial relation between HRV and PP. pressure. Therefore, the baroreceptors will respond Increased sympathetic tone is one potential to a given pressure rise with a reduced afferent nerve mechanism that may lead to simultaneously attenu- activity.39 Thus, there are many different factors,

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