The Effect of Heart Rate on Wave Reflections May Be Determined by the Level of Aortic Stiffness: Clinical and Technical Implications

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1 nature publishing group The Effect of Heart Rate on Wave Reflections May Be Determined by the Level of Aortic Stiffness: Clinical and Technical Implications Theodore G. Papaioannou 1, Charalambos V. Vlachopoulos 1, Nikolaos A. Alexopoulos 1, Ioanna Dima 1, Panagiota G. Pietri 1, Athanassios D. Protogerou 1, Gregory G. Vyssoulis 1 and Christodoulos I. Stefanadis 1 Background Augmentation Index (AIx) is related to cardiovascular diseases, risk, and mortality. AIx is associated with heart rate but the effect of aortic stiffness on this relationship has not been studied. The purpose of our study was to investigate the relationship between AIx and heart rate at different aortic stiffness levels. Methods The study consisted of 425 normotensive and untreated hypertensive subjects. Wave reflections and pulse-wave velocity (PWV) were determined by the Sphygmocor and the Complior systems, respectively. Results AIx was independently associated with heart rate, age, gender, height, mean blood pressure (BP) and the effective reflection site distance (ERD). The population was divided into three groups of those with different PWV levels (tertiles). The regression lines for AIx with heart rate differed significantly between the 3rd and the other two tertiles of PWV (P =.39 for slopes and P =.2 for intercepts). This difference remained significant even after adjustment for age, gender, height, mean BP, and distance of wave reflections. ConclusionS A significantly stronger correlation of AIx with heart rate was observed in subjects with higher levels of aortic stiffness as compared to those with lower levels; namely, the same increase in the heart rate between subjects, induced a greater decrease in the AIx at higher compared to lower PWV levels. The correction of AIx for heart rate should be reconsidered based on the aortic stiffness level. This finding has implications for interventional studies that aim to improve central hemodynamics but simultaneously affect heart rate. Further studies that show acute modifications of heart rate at different arterial stiffness levels are required to support these findings. Am J Hypertens 28; 21: American Journal of Hypertension, Ltd. Arterial wave reflections and their potential relationship to cardiovascular diseases as well as risk are attracting increasing clinical and research interest. Aortic augmentation index (AIx) and augmented pressure (AP) constitute quantitative measures of wave reflections (depending on both timing and intensity of reflected waves). Wave reflections represent a hemodynamic burden that the left ventricle has to confront and they are related to left ventricular function and structure. Consequently, arterial wave reflections have emerged as an independent factor associated with cardiovascular risk and events. 1,2 Wave reflections are increased in the presence of cardiovascular risk factors and they are involved in the pathophysiology of disease states such as coronary artery disease, hypertension, 1 First Department of Cardiology, Unit of Biomedical Engineering and Hypertension Unit, Hippokration Hospital, Medical School, National & Kapodistrian University of Athens, Greece. Correspondence: Theodore G. Papaioannou (theopap@mail.ntua.gr) Received 8 August 27; first decision 24 August 27; accepted 17 November 27; advance online publication 24 January 28. doi:.38/ajh American Journal of Hypertension, Ltd. diabetes, etc. In addition, wave reflections are linked to lifestyle; namely exercise, 3 nutritional habits, 4,5 and smoking. 6 Therefore, there is an emerging need to fully comprehend the physiological cardiovascular characteristics and mechanisms that determine wave reflections and particularly their measures such as AIx. There is ample evidence indicating that AIx and AP depend on several physiological factors, often rendering their interpretation a complex task. Primarily, AIx is inversely related to heart rate 7,8 and body height, 9 and directly to arterial stiffness (pulse-wave velocity (PWV)), peripheral resistance and blood pressure (BP) level. Since the increase in heart rate induces a reduction in AIx, the correction of central AIx for heart rate changes has been previously suggested. 7,11 Whether the influence of heart rate on AIx is independent from arterial stiffness levels is unknown. The hypothesis of this study was that the inverse relationship between indices of wave reflections (AIx, AP) and heart rate is significantly affected by arterial stiffness levels and particularly that lower arterial stiffness attenuates the influence of heart rate on wave reflections (expressed by AIx and AP). 334 MARCH 28 VOLUME 21 NUMBER AMERICAN JOURNAL OF HYPERTENSION

2 Wave Reflections, Heart Rate, and Aortic Stiffness articles Methods Study population. The study population consisted of 425 subjects. In order to examine a wide range of BP and arterial stiffness levels, both normotensive (n = 219) and uncomplicated never-treated hypertensive (n = 26) subjects were studied. The normotensive, clinically healthy subjects were randomly selected from the employee records of two large industries located in Athens, Greece. The hypertensive group consisted of 26 consecutive patients, with uncomplicated, nevertreated essential hypertension, as defined in the Joint National Committee guidelines (JNC 7), who were examined in the Hypertension Unit of our Institution. None of the subjects had any evidence of cardiovascular disease, hypercholesterolemia, diabetes mellitus, or any chronic disease. Furthermore, lipid and fasting blood sugar concentrations were measured in blood samples. Subjects under any vasoactive medication were excluded from the study. All subjects were examined in a quiet, temperature controlled room (21 23 C) and after resting for at least 15 min. The study was approved by the institutional committee on human research and all participants gave informed consent before entering the study. Estimation of wave reflection indices. Wave reflection indices were estimated non-invasively by applanation tonometry of the radial artery and aortic pulse-wave analysis (Sphygmocor System, AtCor Medical, Sydney, Australia). In brief, recording of radial pressure waveforms was performed by a high-fidelity micromanometer placed on the tip of a hand-held tonometer (Millar Instruments, Houston, TX), which was applied to the surface of the skin overlying the radial artery. Several recordings were taken if needed in order to accomplish specific quality control criteria, namely a quality index 85% in accordance to the recommendations of the instrument manual. Three measurements were averaged for the calculation of the parameter used in the analysis. Then, transformation of peripheral pressure waveforms was performed by means of generalized transfer functions, 12 which had been previously validated by using intra-arterially measured pressure waves. 13,14 Calibration of the recorded pressure waveforms was done by using the sphygmomanometric brachial systolic and diastolic BP values, which were measured according to the recommendations of the American Heart Association. 15 As previously reported, this technique presents good reproducibility. 16,17 The following wave reflection indices were determined: AIx, AP, transit time of reflected waves (Tr), effective reflection site distance (ERD) and pulse pressure (PP) amplification. Augmentation index (%) was defined by the formula: AIx = (AP/PP), where AP represents the augmentation (mm Hg) in central systolic pressure due to the return of the reflected wave at the aorta and PP represents the aortic pulse pressure (mm Hg), as illustrated schematically in Figure 1. Tr represents the round trip travel time (ms) of the wave from the heart to the reflection site and back to the central aorta. Both the calculation of AIx and Tr require the determination of the inflection point (shoulder) at the systolic part of the pressure waveform that indicates the merging of backward AP P 2 P 1 Onset of left ventricular ejection A Tr B Dicrotic notch Period Pulse pressure t = T t = t s t = T f Figure 1 Determination of indices indicating intensity and timing of reflected waves by pulse wave analysis. A and B indicate the first and the second inflection points (shoulders) in the systolic part of the waveform respectively. Augmented pressure: AP = P 2 P 1, where P 1 represents the blood pressure at the inflection point which indicates the arrival of reflected waves at the central aorta, and P 2 represents the pressure at the inflection point that corresponds to peak systolic pressure. T and T f indicate the time at the beginning and at the end of the cardiac cycle respectively. Tr is the travel time of the pressure wave from the heart to the reflection site and back to the aorta and ts is the time indicating the end of systole. (reflected) with forward traveling pressure waves. The inflection point corresponding to pressure P 1 (Figure 1) is determined by using the fourth derivative of the pressure signal. Effective reflection site distance was calculated according to the formula: ERD = (Tr PWV)/2, where Tr represents the travel time (s) of pressure waves and PWV represents the carotid-femoral PWV (m/s), as previously described. 18,19 Evaluation of arterial elastic properties. PWV was calculated from measurements of pulse transit time and the distance traveled between two recording sites (PWV = distance (m)/ transit time (s)) using a validated non-invasive device (Complior, Artech Medical, Pantin, France), which allows online pulse wave recording and automatic calculation of PWV. 2 Two different pulse waves were recorded simultaneously at the base of the neck for the common carotid and over the right femoral artery. The distance was defined as: (distance from the suprasternic notch to femoral artery) (distance from carotid artery to the suprasternic notch). PP amplification. Brachial and aortic PP were determined as the difference from the systolic and diastolic BP values, respectively. PP amplification was defined as the ratio of peripheral to central PP. Statistical analyses. Continuous variables have been presented as mean ± standard deviation values, while their distribution was evaluated graphically by means of histograms and statistically by the non-parametric Kolmogorov Smirnov test. PWV tertiles were used to divide the study population into three subgroups for different arterial stiffness levels. Differences among PWV tertiles were evaluated using analysis of variance and post-hoc analysis (Bonferroni corrected Student s t-test for multiple comparisons). Dichotomous variables (i.e., gender) were compared among PWV subgroups by using a two-sided χ 2 test. Males are designated by 1 and females by value. AMERICAN JOURNAL OF HYPERTENSION VOLUME 21 NUMBER 3 MARCH

3 Wave Reflections, Heart Rate, and Aortic Stiffness Bivariate correlations were determined by Pearson s correlation coefficient, whereas multiple linear regression analysis (enter method with forced entry of independent variables in the model) was performed to estimate the independent relationship of aortic AIx, AP, PP, and PP amplification with heart rate (after adjustment for hemodynamic and demographic characteristics). Multicollinearity among variables was assessed by the variance inflation factor and tolerance. The regression lines for AIx, AP, PP, and PP amplification vs. heart rate (unadjusted and adjusted for hemodynamic and demographic parameters) were compared among PWV tertiles. For this purpose, a dummy variable called PWV_groups was created (coded with and 1), indicating the two PWV groups to be compared. After that a new variable PWV_group_HR that is the product of the PWV groups and heart rate (PWV_groups HR) was calculated. Then PWV_groups, heart rate, and PWV_groups_HR were used as independent variables in the regression model with AIx as the dependent variable. Age, gender, mean BP, and ERD were added in the model as additional independent variables for adjustment purposes. The significance levels of the interaction term (PWV_groups HR) and of the dummy variable (PWV_groups) indicate the significant difference of the slopes and intercepts respectively, between the two regression lines. Statistical analysis was performed with SPSS 13 for Windows (SPSS, Chicago, IL). Results Descriptive and hemodynamic characteristics of the study population are presented in Table 1. Determinants of AIx and AP for the total population Parameters associated with AIx in bivariate analysis are shown in Table 2 Stepwise multivariate regression analysis indicated that AIx is significantly associated with: body height (P =.3, R 2 change =.11), age (P =.1, R 2 change =.257), gender (P =.14, R 2 change =.23), mean BP (, R 2 change =.7), PWV (, R 2 change =.8), heart rate (, R 2 change =.82) and ERD (, R 2 change =.135), explaining up to 68% of AIx variation within the study population. The negative sign of the correlation of AIx with gender indicates that women tend to have higher AIx values than men. Variables significantly associated with AP in univariate analysis are reported in Table 2. Multivariate regression analysis revealed that AP is significantly and independently related to body height (, R 2 change =.18), age (, R 2 change =.329), gender (, R 2 change =.124), mean BP (, R 2 change =.4), ERD (, R 2 change =.5), heart rate (, R 2 change =.92) and PWV (, R 2 change =.5) explaining the 73.1% of AP variation within the study population. The negative sign of the correlation of AP with gender indicates women tend to have higher AP values than men. Determinants of PP amplification (in the total population) are shown in Table 2. In multivariate regression Table 1 Descriptive characteristics of the study population (N = 425) Variables Mean ± s.d. Age (years) 46.7 ±.7 Height (cm) ± 9. Aortic systolic BP (mm Hg) 122 ± 22 Aortic diastolic BP (mm Hg) 82 ± 14 Aortic PP (mm Hg) 41 ± 13 Brachial systolic BP (mm Hg) 133 ± 23 Brachial diastolic BP (mm Hg) 81 ± 14 Brachial PP (mm Hg) 53 ± 14 Mean arterial BP (mm Hg) ± 17 Heart rate (b.p.m.) 68.2 ± 9.4 PP amplification 1.32 ±.16 Augmentation Index (%) 25.1 ± 11.1 Augmented pressure (mm Hg).8 ± 7.1 Tr (ms) 143 ± 14 P 1 (mm Hg) 112 ± 18 Effective reflection site distance (m).53 ±.92 Carotid-to-femoral PWV (m/s) 7.1 ± 1.4 Total cholesterol (mg/dl) 24 ± 42 LDL-cholesterol (mg/dl) 135 ± 37 HDL-cholesterol (mg/dl) 48 ± 12 Triglycerides (mg/dl) 7 ± 61 Glucose (mg/dl) 91 ± 14 Values are expressed as mean ± standard deviation. BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; P 1, pressure at the inflection point (shoulder) corresponding to the reflected waves; PP, pulse pressure; Tr, the travel time of the pressure wave from the heart to the reflection site and back to the aorta; PWV, pulse wave velocity. Table 2 Pearson correlation coefficients (P values) are presented for bivariate correlations of augmentation index (AIx), augmented pressure (AP), pulse wave velocity (PWV) and pulse pressure (PP) amplification with demographic, hemodynamic, and vascular parameters Variables AIx AP PWV Age (years).51 (<.2).573 (<.1).56 (<.1) Gender (males).384 (<.1).319 (<.1).1 (.41) Height (cm).433 (<.1).395 (<.1) ns Heart rate (b.p.m.).218 (<.1).2 (<.1).189 (<.1) Mean BP (mm Hg).31 (<.1).522 (<.1).554 (<.1) PWV (m/s).32 (<.1).47 (<.1) AIx (%).856 (<.1).335 (<.1) AP (mm Hg).856 (<.1).47 (<.1) Tr (ms).68 (<.1).619 (<.1).39 (<.1) ERD (m) ns.184 (<.1).883 (<.1) ERD, effective reflection site distance; ns, nonsignificant (P >.5); Tr, the travel time of the pressure wave from the heart to the reflection site and back to the aorta. 336 MARCH 28 VOLUME 21 NUMBER 3 AMERICAN JOURNAL OF HYPERTENSION

4 Wave Reflections, Heart Rate, and Aortic Stiffness articles analysis PP amplification was significantly associated with all the aforementioned variables except from PWV (P =.367) which accounted for 55% of its variation. Differences between tertiles of PWV At first, PWV tertiles were used to divide the study population into three subgroups for different levels of arterial stiffness. The basic characteristics of each PWV tertile are reported in Table 3. Aortic AIx was significantly associated with heart rate at each PWV tertile (tertile-1: r =.25, P =.2, tertile-2: r =.18, P =.31 and tertile-3: r =.43, P =.1). Multiple linear regression analysis indicated that the association of AIx with heart rate remained statistically significant, after adjustment for age, height, gender, mean BP, and ERD, at each PWV tertile. Interestingly, it was found that heart rate variation is responsible for almost 3 6% of AIx variation at low and medium levels of PWV (1st and 2nd tertiles). However, at the higher levels of PWV (3rd tertile) the contribution of heart rate to AIx variation rose to 18.8%. The slope and intercept of the regression lines between AIx and heart rate differed significantly between the 1st vs. the 3rd and the 2nd vs. the 3rd tertile of PWV (P <.5). This difference remained significant after adjustment for age, height, gender, mean BP, and ERD. No difference was observed between the 1st and 2nd tertile in the regression lines for AIx with heart rate. For this reason we focused our further analyses on comparisons between only the 3rd (highest) and the 1st and 2nd (medium to low) PWV tertiles. Again, the regression lines for AIx with heart rate between the two subgroups differed significantly (P =.39 for slopes and P =.2 for intercepts), indicating a stronger correlation of AIx with heart rate at higher compared to lower aortic stiffness levels (Figure 2). These differences remained statistically significant after adjustment for age, height, gender, mean BP, and ERD. Since glucose and lipid levels have been reported to influence pulse waves, a further adjustment of our models was done for glucose, triglycerides, total cholesterols, and LDL values. AIx-HR regression lines still differed significantly between the two groups of different PWV levels (data not shown). Table 3 Differences among tertiles of carotid-to-femoral pulse wave velocity (PWV) PWV Tertile-1 ( m/s) PWV Tertile-2 ( m/s) PWV Tertile-3 ( m/s) P value Age (years) 4.3 ± 8.6*, ** 46. ± 9.5*, *** 52.9 ±.2**, *** <.1 Gender (% males) 51.7*, ** 75.3* 66.7** <.1 Height (cm) 17.7 ± 8.5* 174. ± 9.3*, *** 17.7 ± 8.9***.2 Aortic systolic BP (mm Hg) 6 ± 17*, ** 122 ± 14*, *** 138 ± 23**, *** <.1 Aortic diastolic BP (mm Hg) 72 ± 13*, ** 84 ± *, *** 89 ± 13**, *** <.1 Aortic PP (mm Hg) 34 ± 7*, ** 38 ± 8*, *** 5 ± 16**, *** <.1 Brachial systolic BP (mm Hg) 116 ± 17*, ** 133 ± 15*, *** 15 ± 24**, *** <.1 Brachial diastolic BP (mm Hg) 71 ± 13*, ** 83 ± *, *** 88 ± 13**, *** <.1 Brachial PP (mm Hg) 45 ± 8*, ** 5 ± 9*, *** 62 ± 17**, *** <.1 Mean arterial BP (mm Hg) 88 ± 14*, ** 1 ± 11*, *** 1 ± 16**, *** <.1 Heart rate (b.p.m.) 65.6 ± 8.6*, ** 68.5 ± 8.9* 7.5 ±.2** <.1 PP amplification 1.36 ±.17** 1.33 ±.16*** 1.27 ±.14**, *** <.1 Augmentation Index (%) 21.2 ± 11.8** 23.5 ±.7*** 29.1 ±.2**, *** <.1 Augmented pressure (mm Hg) 7.6 ± 5.1** 9.4 ± 5.3*** 15.1 ± 8.1**, *** <.1 Tr (ms) 15 ± 16*, ** 141 ± 12*, *** 137 ± **, *** <.1 P 1 (mm Hg) 98 ± 15*, ** 113 ± 12*, *** 123 ± 18**, *** <.1 ERD (m).421 ±.55*, **.51 ±.46*, ***.592 ±.72**, *** <.1 Carotid-to-femoral PWV (m/s) 5.6 ±.5*, ** 6.9 ±.3*, *** 8.6 ± 1.**, *** <.1 Total cholesterol (mg/dl) 193 ± 38*, ** 27 ± 46* 212 ± 39**.2 LDL-cholesterol (mg/dl) 128 ± ± ± HDL-cholesterol (mg/dl) 48 ± ± ± Triglycerides (mg/dl) 87 ± 44*, ** 8 ± 61*, *** 125 ± 7**, *** <.1 Glucose (mg/dl) 86 ± *, ** 92 ± 12* 95 ± 17** <.1 Values are presented as mean ± s.d. P value indicates overall statistically significant differences among PWV tertiles. BP, blood pressure; ERD, effective reflection site distance; HDL, high-density lipoprotein; LDL, low-density lipoprotein; P 1, pressure at the inflection point (shoulder) corresponding to the reflected waves; PP, pulse pressure; PWV, pulse wave velocity; Tr, the travel time of the pressure wave from the heart to the reflection site and back to the aorta. *significant (P <.5) difference between 1st and 2nd PWV tertiles. **significant (P <.5) difference between 1st and 3rd PWV tertiles. ***significant (P <.5) difference between 2nd and 3rd PWV tertiles. AMERICAN JOURNAL OF HYPERTENSION VOLUME 21 NUMBER 3 MARCH

5 Wave Reflections, Heart Rate, and Aortic Stiffness a Augmentation index (%) st and 2nd tertiles of PWV (<7.5 m/sec) r =.172 P = AP was marginally unrelated (r =.111, P =.6) to heart rate at low-medium arterial stiffness (1st and 2nd PWV tertiles). On the contrary AP was significantly associated with heart rate at the higher levels (3rd PWV tertile) of arterial stiffness (r =.295, ). The regression lines for AP with heart rate between the two subgroups (1st and 2nd vs. 3rd PWV tertiles) differed significantly (P =.1 for slopes and for intercepts), indicating that heart rate influences AP to a greater degree at higher compared to lower aortic stiffness levels (Figure 3). These differences were statistically significant after adjustment for age, height, gender, mean BP, and ERD. The results were unaltered after further adjustment for glucose and lipid values (data not shown). AIx represents the hemodynamic result of the merging of the forward with the backward traveling (reflected) wave. Thus, we further examined the association of heart rate with P 1 (pressure at the inflection point which corresponds with peak flow). It was found that P 1 is not related significantly to heart rate in the total population or in each stiffness group (PWV tertiles) after adjustment for age, gender, mean BP, and ERD (Table 4). PP amplification was significantly related to heart rate in both groups of low and high arterial stiffness (r =.328, and r =.539, respectively). The degree of this association was similar in both groups with and without adjustment for age, gender, mean BP, height, and Tr. b Augmentation index (%) 3rd tertile of PWV ( 7.5 m/sec) 5 r = Figure 2 Correlation of aortic augmentation index with heart rate at two different levels of aortic stiffness as indicated by carotid-to-femoral pulse wave velocity (PWV): (a) PWV < 7.5, (1st and 2nd tertiles of PWV) and (b) PWV 7.5 m/s (3rd tertiles of PWV). r, Pearson correlation coefficient; P, the significance level. a Augmented pressure (mm Hg) st and 2nd tertiles of PWV (<7.5 m/sec) r =.111 P = b Augmented pressure (mm Hg) 3rd tertile of PWV ( 7.5 m/sec) r = Figure 3 Correlation of aortic augmented pressure with heart rate at two different levels of aortic stiffness as indicated by carotid-to-femoral pulse wave velocity (PWV): (a) PWV < 7.5, (1st and 2nd tertiles of PWV) and (b) PWV 7.5 m/s (3rd tertile of PWV). r, Pearson correlation coefficient; P, the significance level. Table 4 Multivariate regression analysis of indices of wave reflections and BP pulsatility (dependent variables) with heart rate (independent variable) after adjustment for age, gender, height, mean blood pressure, and effective reflection site distance (covariates) Indices of wave reflections and BP pulsatility Aortic AIx Aortic AP Low-medium aortic stiffness (1st and 2nd PWV tertiles) N = 281 b =.333, b =.36, Brachial PP b =.81, P =.133 Aortic PP b =.176, PP amplification b =.446, Pressure at the inflection point b =.2, P =.126 High aortic stiffness (3rd PWV tertile) N = 144 b =.518, b =.469, b =.95, P =.171 b =.288, b =.632, b =.11, P =.619 P values for slopes and intercepts.5 and.8.3 and <.1 Relationship between heart rate and PWV In order to clarify the possible confounding effect of heart rate on PWV we performed an additional regression analysis with PWV as a dependent variable. In the total population PWV was related to age, gender, AIx, AP, Tr, mean BP, central and peripheral PP, PP amplification, and heart rate (Table 2). However, multivariate analysis revealed that PWV was independently related only to age (, R 2 change =.96), gender (P =.3, R 2 change =.12), mean BP (, R 2 change =.37) and Tr (P =.28, R 2 change =.7) and not with AIx (P =.939) or heart rate (P =.448). PWV was not related significantly to the heart rate in separate multivariate analysis at each PWV tertile. Discussion This study has demonstrated that the association of AIx with heart rate is significantly influenced by the aortic stiffness level. Specifically, for subjects with high levels of aortic stiffness (3rd tertile of carotid-to-femoral PWV), the heart rate explained up to 19% of AIx variance, while only 3% of AIx variance was explained by heart rate variation in subjects with lower aortic stiffness levels. The findings of this study have major physiological and clinical implications. Mechanisms technical implications The present findings are in line with the different response of peripheral and central PP to heart rate changes at various levels of arterial stiffness (as we have previously shown). 24 More specifically, there was found a combined effect from arterial stiffness and heart rate on the amplitude of pressure waveform (PP) in vivo and in vitro, indicating a greater effect ns.94 and.13 No collinearity was observed among the independent variables. AIx, augmentation index; AP, augmented pressure; b, standardized coefficient; BP, blood pressure; ns, nonsignificant; PP, pulse pressure. ns ns 338 MARCH 28 VOLUME 21 NUMBER 3 AMERICAN JOURNAL OF HYPERTENSION

6 Wave Reflections, Heart Rate, and Aortic Stiffness articles of the heart rate on PP at higher compared to lower arterial stiffness levels. 24 However, that observation was true only for central PP, while peripheral PP was not related significantly to heart rate after adjustment for mean BP and stroke volume. 24 In this study, brachial PP was not related significantly to heart rate, while aortic PP was (Table 4), a finding that is in line with previously reported data. 24 A question that remains to be answered is whether acute changes of heart rate (e.g., pacing) induce different hemodynamic effects (e.g., on wave reflections) at different levels of arterial stiffness regardless of BP and LV contractility. Previous studies reported that increasing heart rate (through pacing) induces a decrease in AIx, 7,8 without, however, accounting for arterial stiffness levels. Similarly, other observational studies that have also reported an inverse relationship for aortic and carotid AIx with heart rate, 11,25 have not accounted for arterial stiffness level. More specifically, in the study by Wilkinson et al., 7 the investigated population consisted of middle aged and elderly subjects (mean age 63 years) with an average peripheral systolic pressure >135 mm Hg for the examined range of heart rate (6 1 b.p.m.) and mean AIx >2% for heart rates <7 b.p.m. Although arterial stiffness levels were not assessed in that study, it could be speculated that this population with the aforementioned characteristics (age, systolic pressure, and AIx), is probably characterized by high arterial stiffness. In that case and according to our findings, a stronger relationship of AIx with heart rate might be implied, but it might not necessarily be evident in (or applicable to) subjects with quite low arterial stiffness levels (i.e., younger subjects <4 years or subjects with lower BP levels). Due to this reported effect of heart rate upon AIx, corrections of aortic and carotid AIx are now used in several different populations regardless of their arterial stiffness levels. The significantly weaker association of AIx with heart rate in subjects with lower stiffness compared to those with greater stiffness suggests that the effect of heart rate on AIx and (consequently the mathematical correction of the latter for heart rate) might need to be different among groups of subjects with different arterial stiffness levels. Consequently a statistical correction for heart rate of the correlations between unadjusted AIx and other variables (by using multivariate statistical models) might be a more preferable procedure than applying the heart rate corrected AIx in populations with low arterial stiffness. The mechanisms involved in the differential association of AIx with heart rate at different levels of aortic stiffness are difficult to fully elucidate. However, this finding could bear a resemblance to the response of a damp spring-mass oscillating physical model at different frequencies. In such a physical model, the change in the amplitude of the oscillation caused by the changes in the frequency of the oscillation (ω), are dependent on the damping coefficient (ζ) of the model. For example, the same increase in frequency (i.e., a respective increase in heart rate) induces a greater reduction in the amplitude of the oscillation (i.e., a respective decrease in AIx) at the lower compared to higher damping coefficient (i.e., a respective stiffness). A possible interaction between heart rate and PWV might be a confounding underlying mechanism that could have influenced the relationship of AIx with heart rate at different PWV levels. However, in a separate analysis, no significant independent relation between PWV and heart rate was observed. While an association between PWV and heart rate has been described, 26,27 this has not been found in all studies. 28,29 Clinical implications An elevation of AIx and consequently an increase in central BPs has been associated with several pathological conditions and diseases, while several studies suggest that high values of AIx are related to increased cardiovascular risk and mortality. 1,3 For these reasons, the attenuation of increased arterial wave reflections has been investigated extensively, by using pharmaceutical interventions or lifestyle modifications. However, it should be noted that the resulting changes in AIx by such interventions, are either due to direct mechanisms (vasoactive), or through indirect ones, such as the alteration in heart rate. In BP lowering interventions, the less favorable clinical outcome with heart rate-lowering drugs may be associated with higher AIx. 31 Importantly, according to the results of our study, such effects may be more pronounced in subjects with increased arterial stiffness, and most likely this was the case in the CAFÉ study, in which the hypertensive patients had high aortic stiffness (mean PWV > m/s). Since the findings of this study mainly concern normotensive and untreated hypertensive subjects, it may not be possible to directly extrapolate the results to populations with other characteristics, such as patients with cardiovascular disease, diabetes, or dyslipidemia. Finally, it has been reported previously that a dissociation of AIx with PWV may exist 32 and also that vasoactive drugs may change AIx relatively independent of aortic PWV. 33 These observations might be explained in part by the findings of this study, namely by a possible underlying differential effect of heart rate on AIx at different levels of arterial stiffness. A significantly different correlation of heart rate with AIx and AP was found between groups of subjects with different levels of aortic stiffness independent of age, gender, height, mean BP, and distance of wave reflections. Hence the correction of AIx for heart rate at 75 b.p.m. might be reconsidered based on the level of aortic stiffness. The differential response of AIx to heart rate variation at different levels of arterial stiffness probably has major clinical implications too, especially in interventional studies that aim to reduce wave reflections and that concurrently affect heart rate. The present findings, however, remain to be further enhanced by acutely modifying in vivo heart rate at different levels of arterial stiffness. Disclosure: The authors declared no conflict of interest. 1. London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME. Arterial wave reflections and survival in end-stage renal failure. Hypertension 21; 38: Stamatelopoulos KS, Kalpakos D, Protogerou AD, Papamichael CM, Ikonomidis I, Tsitsirikos M, Revela I, Papaioannou TG, Lekakis JP. The combined effect of augmentation index and carotid intima-media thickness on cardiovascular risk AMERICAN JOURNAL OF HYPERTENSION VOLUME 21 NUMBER 3 MARCH

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