6 In the CAFE study, the main difference in central aortic pressures resulted from an increase in AIx ⴝ augmentation index pressure wave reflections (

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1 Journal of the American College of Cardiology 9 by the American College of Cardiology Foundation Published by Elsevier Inc. Vol. 54, No. 8, 9 ISSN /9/$36. doi:116/j.jacc CME Impact of Heart Rate on Central Aortic Pressures and Hemodynamics Analysis From the CAFE (Conduit Artery Function Evaluation) Study: CAFE-Heart Rate Bryan Williams, MD, Peter S. Lacy, PHD, for the CAFE and the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) Investigators Leicester, United Kingdom Objectives The CAFE (Conduit Artery Function Evaluation) study showed less effective central aortic pressure lowering with atenolol-based therapy versus amlodipine-based therapy in people with hypertension. The present study examined the importance of heart rate () as a determinant of this effect. Background Recent analyses have suggested that beta-blockers are less effective at reducing cardiovascular events than alternative blood pressure (BP)-lowering therapies. There has been much debate about the mechanism for this shortfall in benefit and specifically the role of lowering by beta-blockers. Methods Central pressures were derived from brachial pressure and radial pulse wave analysis in 2,73 patients, and 7,146 measurements were recorded and analyzed over follow-up for up to 4 years. Results There was no impact of on brachial systolic or pulse pressures; however, there was a highly significant inverse relationship between and central aortic systolic and pulse pressures (p.1). This was dependent on a strong inverse relationship between and augmentation index, indicative of increased wave reflection at lower s. Multiple regression, adjusted for brachial BP, showed to be the major determinant of central pressures. Moreover, and brachial BP accounted for 92% of the variability in central systolic and pulse pressures. Consequently, drugrelated differences in central aortic pressures were markedly attenuated after adjustment for. Conclusions When comparing beta-blocker based treatments with other BP-lowering strategies, reduction with beta-blockers is a major mechanism accounting for less effective central aortic pressure reduction per unit change in brachial pressure. (J Am Coll Cardiol 9;54:5 13) 9 by the American College of Cardiology Foundation Beta-blockers have been a primary treatment for hypertension for many years. However, recent analyses have suggested that beta-blocker based therapy may be less effective at preventing cardiovascular events when compared with alternative blood pressure (BP)-lowering treatments in peosee page 714 ple with hypertension (1 5). The United Kingdom National Treatment Guidelines in 6 recommended that betablockers should no longer be considered a suitable initial therapy for the treatment of hypertension (6). There has been much speculation about mechanisms for this shortfall Continuing Medical Education (CME) is available for this article. From the Department of Cardiovascular Sciences, University of Leicester School of Medicine, and the Leicester NI Cardiovascular Biomedical Research Unit, Leicester, United Kingdom. Manuscript received November 19, 8; revised manuscript received February 11, 9, accepted February 23, 9. in cardiovascular protection, especially stroke prevention, with beta-blockers in hypertensive patients. In the CAFE (Conduit Artery Function Evaluation) study, we have previously shown that the beta-blocker atenolol was less effective at lowering central aortic systolic and pulse pressures (PPs) when compared with alternative BP-lowering treatment, despite similar brachial BP control (7). These findings are consistent with data from previous smaller-scale studies of shorter duration (8 11). Further analysis of the CAFE study suggested that central pressures may be an independent predictor of clinical outcomes in hypertensive patients (7). These findings suggest that the shortfall in benefit from beta-blockers could relate to less effective central aortic pressure lowering, despite seemingly similar effects as other drugs treatments on brachial BP. If this is the case, then important questions follow. What is the mechanism for the less effective reduction in central aortic pressures with beta-blockers? Is this mechanism specific to atenolol, or is it more broadly applicable to all beta-blockers?

2 6 In the CAFE study, the main difference in central aortic pressures resulted from an increase in AIx ⴝ augmentation index pressure wave reflections (augbp ⴝ blood pressure mentation index [AIx]) with ⴝ heart rate atenolol-based therapy, resulting PP ⴝ pulse pressure in augmentation of central aortic systolic and PPs. Previous studies have demonstrated that AIx is inversely related to heart rate () (12,13), suggesting that reduction may be the main mechanism accounting for less effective central pressure reduction with beta-blocker based therapies. These observations prompt further questions. How much of the difference between atenolol- versus amlodipine-based therapy in the CAFE study could be attributed to the differences in between treatments? After adjusting for differences, was there any residual impact of the 2 BP-lowering regimens on central aortic pressures and hemodynamics? The answer to these questions clearly has important implications with regard to the potential impact of therapeutic manipulation on central aortic pressures and hemodynamics in people with hypertension. The present study thus examined the hypothesis that was a major factor accounting for the differential impact of BP-lowering treatments on central aortic pressures and hemodynamics in the CAFE study. Abbreviations and Acronyms Baseline for the CAFEfor Population Table 1 Demographics Baseline Demographics the CAFE Population Atenolol Based (n ⴝ 1,31) Amlodipine Based (n ⴝ 1,42) Demographics and clinical characteristics Women 8 (.%) 189 (18.3%) ⱕ. 367 (35.2%) 381 (37.%). 675 (64.8%) 6 (63.%) Mean (SD) 62.9 (8.2) 62.6 (8.3) (yrs) White (cm) 892 (85.6%) 1.7 (8.7) 886 (85.9%) 1.2 (9.4) (kg) 84.3 (15.7) 84.6 (14.7) BMI (kg/m2) 29.1 (4.7) 29. (4.5) Current smoker 267 (25.6%) 251 (24.3%) Previous smoker 438 (42.%) 448 (43.5%) Never smoked 358 (34.4%) 352 (34.1%) Systolic blood pressure (mm Hg) 161. (18.4) (16.6) Diastolic blood pressure (mm Hg) 92.6 (9.8) 92.4 (9.6) Heart rate (beats/min) 71.2 (12.4) 71.8 (12.3) Cigarettes/week among current smokers 82. (68.6) 92.6 (75.5) Alcohol consumption (U/week) 11.8 (14.9) 11.5 (14.3) Total cholesterol (mg/dl) (38.7) (42.5) LDL cholesterol (mg/dl) (34.8) (34.8) HDL cholesterol (mg/dl).3 (15.5).3 (15.5) (88.6) (88.6) Triglycerides (mg/dl) Glucose (mg/dl) 11 (38) 11 (38) Creatinine (mg/dl) 1.8 (8) 1.9 (9) Medical history Methods The details of the CAFE study patient population and study design and procedures have been previously published (6) and are briefly summarized below. CAFE study population and design. The CAFE study was a substudy of the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study (14). Data on central aortic hemodynamics was available from 2,73 participants recruited from 5 ASCOT study centers in the United Kingdom and Ireland. These data form the basis of the present analysis and were collected over a median follow-up of 3 years. At baseline, the patient population was hypertensive, of whom the majority was previously treated (%). The patients also had 3 additional cardiovascular risk factors to qualify for randomization to 1 of 2 BP-lowering strategies, using a prospective, randomized, open, blinded end point design: 1) a regimen of amlodipine, adding perindopril as required; or 2) a regimen of atenolol, adding bendroflumethiazide-k as required. Additional BPlowering therapies were common to both treatment arms according to a pre-specified algorithm (14). Antihypertensive treatment was titrated to achieve a target BP ( 1/ mm Hg for people without diabetes and 1/ mm Hg for people with diabetes). The patient demographics are shown in Table 1. All patients gave written informed consent, and approval for the study was granted by local research ethics committees at each ASCOT study center. Ethical approval was also granted by the United Kingdom Multi-Center Ethics Committee. Previous stroke/tia 11 (9.7%) 76 (7.4%) Diabetes 251 (24.1%) 252 (24.4%) LVH (echocardiogram or ECG)* 256 (24.6%) 237 (23.%) Atrial fibrillation 6 (.6%) 9 (.9%) 272 (26.1%) 271 (26.3%) Peripheral vascular disease 59 (5.7%) 61 (5.9%) Other relevant cardiovascular disease 27 (2.6%) 22 (2.1%) Mean (SD) number of risk factors 3.7 (.9) 3.7 (.9) ECG abnormalities other than LVH Drug therapy Previous antihypertensive treatments None (9.6%) 19 (1.6%) (47.6%) 482 (46.8%) ⱖ2 446 (42.8%) 4 (42.7%) Lipid-lowering therapy 1 (11.5%) 1 (11.6%) Aspirin use 274 (26.3%) 244 (23.7%) *Left ventricular hypertrophy (LVH) by echocardiography was assessed as 116 g/m2 in men and 14 g/m2 in women. Electrocardiogram (ECG) LVH was defined using either Cornell voltage duration product ( 2,4) or Sokolow Lyon criteria ( 38 mm); included evidence of left ventricular strain pattern, abnormal Q waves, evidence of left bundle branch block, and ST-T changes compatible with ischemic heart disease (ST-T depression, negative or biphasic T waves); assessed using a validated questionnaire or from evidence of a recent history of surgical intervention for peripheral vascular disease. BMI body mass index; CAFE Conduit Artery Function Evaluation; HDL high-density lipoprotein; LDL low-density lipoprotein; TIA transient ischemic attack. Brachial BP, radial pulse wave analysis, and derivation of central aortic pressures and hemodynamic indexes. Brachial BP was measured using a validated semi-automated oscillometric device (Omron 5CP, Omron, Kyoto, Japan) as specified in the ASCOT study protocol (15). The CAFE study used radial artery applanation tonometry and pulse wave analysis (16,17) to derive central BPs and other parameters, as previously described (Online Appendix).

3 This method generates central aortic pressure waveforms from the radial pressure waveform using a previously validated transfer function (18,19). The central pressure waves were analyzed to identify the outgoing and reflected components and to calculate the AIx (i.e., the proportion of the central PP that is attributable to pulse wave reflection [ P], i.e., [AIx ( P/PP) ]) (Online Fig. 1). PP amplification was calculated as the ratio of brachial to central PP. An average of 3.4 applanation tonometry measurements per patient were obtained at scheduled ASCOT study follow-up visits. Typical interobserver variability at individual ASCOT centers was mm Hg for central systolic pressure and % for AIx. This is consistent with our previously published data using this technique (). Statistical methods. Statistical analyses were performed in collaboration with the ASCOT Study Coordinating Center at A Science, Goteborg, Sweden, using the SAS computer program version 8.2 (SAS Institute Inc., Cary, North Carolina). Analysis of the impact of on brachial BP, central aortic pressures, and hemodynamic indexes. This analysis used 3 complementary strategies: 1) We examined the relationship between as a continuous variable and brachial BP, central aortic pressures, and hemodynamic indexes. Data from every CAFE study measurement (n 7,146) relating to these indexes, blinded to treatment allocation, were included in the analysis. 2) Multiple stepwise regression was performed to rank and quantify the impact of on brachial and central aortic pressures and hemodynamic indexes. 3) Data from the CAFE study was adjusted for to assess the residual impact of drug therapy on central aortic pressures and hemodynamics. A Brachial mmhg 1 Central 1 11 Brachial, y = -.6x , R2 =.56, p=.9 Central, y = -.3x , R2 =.97, p<.1 B (min-1) mmhg Brachial Central 1 Brachial, y = -.3x , R2 =.2, p=.4 Central, y = -.3x + 64., R2 =.96, p<.1 (min-1) Figure 1 7 Relationship Between and Brachial or Central Pressures (Mean ⴞ SD) (A) Relationship between brachial (red circles) and central aortic (blue circles) systolic blood pressure and heart rate (). (B) Relationship between brachial (red circles) and central aortic (blue circles) pulse pressure and. Data are grouped into 1 beats/min heart rate increments (mean SD).

4 8 The relationship between and brachial versus central pressures. The relationship of with brachial and central pressures is shown in Figure 1. The data encompass all measurements performed during the CAFE study followup. The data plots were very dense, thus for clarity of presentation, the data were grouped into increments of increasing (1 beats/min increments). Importantly, the regressions of the relationships did not differ when comparing the grouped and raw data plots. There was no significant impact of reducing on brachial systolic BP (.6 mm Hg per 1 beats/min decrease in ) (Fig. 1A). By contrast, there was a 5-fold greater increase in central systolic pressure per unit change in ( 3. mm Hg per 1 beats/min decrease in ). A similar dissociation between the impact of on brachial and central PP was also observed (Fig. 1B). Figure 2 shows the differences between brachial and central pressures, plotted as a function of. Importantly, at lower s, the difference between brachial and central pressure progressively decreased, so that central pressure approached brachial pressure at the lowest s. For univariate analyses, data were grouped into deciles of, and the relationship between and hemodynamic variables was analyzed using linear regression. Regression lines were also fitted to plots of raw data. For multivariate analysis, stepwise multiple linear regression was used. Variables entered into the model were determined by linear correlation analyses. Continuous data variables between BP-lowering regimens were compared using nonpaired Student t tests. Where stated, data were adjusted for using general linear modeling before comparisons were made. Data are presented as mean (95% confidence interval) or mean SD as stated and a value of p.5 was considered significant. Results The baseline characteristics of the CAFE study population according to their randomized BP-lowering treatment allocation are shown in Table 1. The 2 treatment groups were well matched with respect to their demographics, clinical characteristics, and previous medication. Brachial-Central SBP (mmhg) A y =.25x - 5.7, R2 =.35, p< B Brachial-Central PP (mmhg) y =.28x - 6.7, R2 =.422, p< (min-1) Figure 2 Relationship Between and the Difference Between Brachial and Central Pressures Relationship between heart rate () and the difference between brachial and central systolic blood pressure (SBP) (A) or brachial and central pulse pressure (PP) (B).

5 Relationship between and components of the central pressure waveform. To investigate the mechanisms involved in the changes in central pressure with variation in, we next analyzed the components of the central pressure waveform in relation to. There was minimal impact of on the amplitude of the outgoing pressure wave (P1 height). However, there was a strong and significant inverse relationship between and the amplitude of pressure wave reflections (augmentation), which increased by 3 mm Hg per 1 beats/min reduction in (Fig. 3A). This finding suggests that the main impact of reduction was on the reflected wave, rather than the incident pressure wave. Consistent with this observation, there was a marked increase in AIx with reducing : 4.9% per 1 beats/min reduction in (Fig. 3B). The relative contribution of to central pressures and hemodynamic variables. To further evaluate the contribution of to central pressures and hemodynamics, we performed stepwise multiple linear regression (Table 2). After accounting for brachial BP, was the major determinant of central systolic and pulse pressures, accounting for 5% and 9% of the variability in these parameters, respectively. was also a major determinant of pressure wave reflections (augmentation and AIx) and PP amplification, accounting for 26%, 34%, and 54%, respectively of the variability in these parameters. Of importance, in this analysis, the BP treatment regimen was a much less powerful determinant of central pressures and wave reflections, accounting for no more than.5% of the variability (i.e., at least 1-fold less important than the impact of ). Comparison of central pressures and hemodynamic variables between BP-lowering treatment arms before and after adjustment for. To further evaluate the relative contribution of as a determinant of central pressures, the differential impact of the 2 BP-lowering treatment regimens on central pressures and wave reflections was resolved after adjusting the data for differences (Table 3). After A mmhg Outgoing Reflected Outgoing, y = -.3x , R2 =.2, p<.1 1 Reflected, y = -.3x , R2 =.3, p<.1 1 (min-1) B AIx (%) 1 y = -.49x , R2 =.34, p<.1-1 (min-1) Figure 3 9 Relationship Between and Outgoing or Reflected Pressure Wave Components (A) Relationship between heart rate () and the outgoing pressure wave (P1 height, red circles) and and the reflected pressure wave (augmentation, blue circles). (B) Relationship between augmentation index (AIx) and. 11 1

6 71 Stepwise Regression of Central Pressures and Hemodynamic Variables Variables Table 2 Multiple Stepwise Multiple Analysis Regression Analysis of Central Pressures and Hemodynamic Model and Predictors Regression Coefficient SE F Value p Value R2 Change (%) Central systolic pressure; adjusted r.95, p , , , Central PP; adjusted r2.94, p.1.72, , Augmentation; adjusted r2.69, p , Smoker* ECG other Augmentation index; adjusted r2.55, p , Smoker ECG other PP amplification; adjusted r2.66, p , ECG other Smoker *Current or recent (in the last year) smoker; abnormalities on electrocardiogram (ECG) other than left ventricular hypertrophy including evidence of left ventricular strain pattern, abnormal Q waves, evidence of left bundle branch block, and ST-T changes compatible with ischemic heart disease (ST-T depression, negative or biphasic T waves). Br brachial; heart rate; PP pulse pressure; SBP systolic blood pressure; SE standard error. adjustment, the differences in central systolic and PPs between treatment arms were no longer significant, and the differences in augmentation, AIx, PP amplification, and the brachial- central aortic systolic and pulse pressure changes were markedly attenuated. Taken together, these data suggest that is an important determinant of central aortic systolic and PPs and

7 711 BP-Lowering Comparison Comparison of Treatment Central Pressures Arms Before and and Hemodynamic Afterand Adjustment Variables for Between Heart Rate Between of Central Pressures Hemodynamic Variables Table 3 BP-Lowering Treatment Arms Before and After Adjustment for Heart Rate Unadjusted Parameter Adjusted Atenolol Amlodipine p Value Atenolol Amlodipine ( ) ( ) ( ) ( ).7 Central pulse pressure (mm Hg) 46.4 ( ) 43.4 ( ) 44.6 ( ) 45.2 ( ).2 Augmentation (mm Hg) 15.4 ( ) 11.5 ( ) 13.7 ( ) 13.1 ( ).2 Augmentation index (%) 31.9 ( ) 25.3 ( ) 29.3 ( ) 27.8 ( ) Pulse pressure amplification Central systolic BP (mm Hg) p Value 1.21 ( ) 1.31 ( ) 1.25 ( ) 1.27 ( ) Brachial-central SBP (mm Hg) 8.3 ( ) 12. ( ) 9.6 ( ) 1.8 ( ) Brachial-central PP (mm Hg) 8.9 ( ) 12.8 ( ) 1.3 (1. 1.5) 11.4 ( ) Values are mean (95% confidence interval). BP blood pressure; other abbreviations as in Table 2. was the main determinant of the difference between central and brachial pressures between treatment arms in the CAFE study. Discussion Within a major clinical outcomes trial, this is the first study to define the impact of drug-related changes in, on central aortic pressures and hemodynamics, in hypertensive patients. With over 2, patients and over 7, measurements, this study had abundant statistical power to test its hypotheses. The data clearly demonstrate the powerful influence of, across the physiological range, on central aortic pressures and wave reflections in hypertensive patients, despite minimal effects on brachial pressures. We show that is inversely related to central aortic systolic and PPs. Lower s are also associated with reduced PP amplification; thus, at lower s, the central aortic systolic pressure becomes closer to the brachial systolic pressure. Importantly, there was minimal impact of on the outgoing pressure wave height (P1 height), showing only a minor increase with reduced. However, the inverse relationship between and indexes of central pressure wave reflection (i.e., augmentation) were much stronger, consistent with increased wave reflection at lower s. Remarkably, the slopes for the relationship between and central aortic systolic pressure or magnitude of wave reflection (augmentation) were identical ( 3 mm Hg per 1 beats/min reduction in ), suggesting the importance of wave reflection in mediating the -related change in central aortic systolic pressure. This finding that central pressure wave reflection is strongly influenced by is supported by data from cross-sectional studies with data stratified by (21) and studies of cardiac pacing in humans, which suggested that AIx declines by 4% to 5% per 1 beats/min increase in (12,13); the data for AIx from the present study are similar at 4.9% per 1 beats/min reduction in. Interestingly, in a recent population study, was the most powerful modifiable predictor of AIx, central systolic pressure, and central PP (22). Impact of versus treatment regimen. Multiple regression analysis confirmed the relative importance of after BP itself, as a key determinant for all central hemodynamic parameters. Moreover, adjusting the CAFE study data for markedly attenuated the difference in central pressures between the 2 BP-lowering treatment regimens. This suggests that this difference was primarily driven by differences in, although some residual effects remained. It is conceivable that unmeasured hemodynamic factors such as aortic stiffness and systemic vascular resistance/remodeling, which could be differentially influenced by drug treatments, may have accounted for some of this residual variability (1,23). Mechanisms for the inverse relationship between and central aortic pressures. We suggest 2 mechanisms that could account for the elevation in central pressures with reduced : first, reducing prolongs cardiac ejection duration, but has no major effect on pulse velocity (7,24). This increases the likelihood of a greater proportion of the reflected wave appearing in late systole for any given pulse wave velocity. Beta-blockade also decreases the dp/dt during ventricular ejection, and this could delay the time to the peak of the outgoing wave (1,25). This could also increase central systolic pressure by increasing the probability of coincidence of the reflected wave with late systole. Our finding of an increased AIx with beta-blockade is consistent with this hypothesis. Second, the less effective lowering of central aortic systolic and pulse pressures in patients with lower s is consistent with basic physiology. According to the derivation of Poiseuille s law, BP is the product of cardiac output peripheral resistance, where cardiac output is the product of stroke volume and. When is reduced by drug therapy (e.g., a beta-blocker) mean arterial pressure is maintained by an increase in stroke volume (26) a phenomenon readily observed in patients with complete atrio-ventricular heart block. In younger patients with compliant conduit arteries, this increase in stroke volume can be accommodated. Indeed, in conditioned athletes, a combination of increased aortic compliance and peripheral vasodilation prevents a marked rise in AIx and central aortic pressure despite very low s and markedly increased stroke volumes (27). This represents perfect physiological adaptation to a reduced. In contrast, most hypertensive patients are not conditioned athletes, and in the CAFE study were older with stiffened conduit arteries. In this setting, a reduction in will result in the increased stroke volume being ejected into a less compliant proximal aorta, resulting in a rise in central aortic systolic and PPs. We suggest that these are the 2 principal mechanisms accounting

8 712 for the inverse relationship between and central aortic systolic and PPs in the CAFE study. Moreover, we suggest that this inverse relationship would be accentuated if changes are restricted by drugs (i.e., beta-blockers) during exercise, when the need to increase cardiac output could only be met by an increase in stroke volume. These considerations are of clinical importance given that central PP showed a significant association with clinical outcomes in the CAFE study and other studies (28,29). Is this data relevant to all beta-blockers? The present study raises important questions as to whether similar effects would have been observed with beta-blockers other than atenolol, notably vasodilating beta-blockers. Our data suggest that the impact of on central aortic pressure is very powerful and consistent across the physiological range, irrespective of treatment allocation in this study. Other studies using invasive monitoring have shown that in patients receiving beta-blockers, the use of powerful vasodilators cannot overcome the impact of reduction on wave reflection and central pressures (). By contrast, a small number of previous studies comparing vasodilating and nonvasodilating betablockers have suggested a more beneficial influence of vasodilating beta-blockers on central pressures (31,32). However, these studies were small scale and underpowered, and the differences in central pressures and wave reflections between the different beta-blockers could be accounted for by the lesser reductions in with vasodilating beta-blockers and/or differences in brachial BP. Study limitations. We recruited predominantly white men. However, our regression analysis suggests that the direction of change in central pressures and hemodynamics was the same for women. It is unclear whether similar findings would have been observed in other ethnic groups. Nevertheless, we cannot rationalize why a mechanism that appears to be so dependent on would be different in other ethnic groups. Our patient population was also older, with a mean age of 63 years at baseline. It is conceivable that in younger people with more compliant conduit arteries there would be a lesser impact of lower s on central aortic pressure. These important considerations need further evaluation. We used noninvasive methods to derive central aortic pressure from the radial pulse wave, calibrated to brachial BP. It has to be considered whether the mathematical transfer function used to derive central hemodynamic indexes could be sensitive to, or confounded by, changes in. The mathematics involved are beyond detailed discussion here but use a transfer function to calculate central pressures from individual radial pressure waveforms that is uninfluenced by the number of waveforms as a function of time. Although, to our knowledge, there have been no specific studies to assess impact of on central pressures comparing the methods here with direct invasive measurements, there have been invasive measurements of central aortic pressures in humans in response to changes in. In these studies, increasing via cardiac pacing has been shown to reduce central aortic pressure (12). Moreover, previous invasive studies have shown that betablocker treatment increased (rather than reduced) central aortic pressures (33). These directional changes are consistent with our findings. Furthermore, data from studies directly analyzing carotid or invasively acquired central pressure waves have documented reduced pressure amplification with betablockade (24,33), consistent with our data. Other studies have also implicated as a major factor modulating pressure amplification (13,21,34,35). Finally, our study examines the association between ontreatment and central pressures. It does not directly assess the change in central pressure in response to a treatmentinduced change in in individual patients. This would have been difficult to do because of confounding due to associated changes in BP per se as a consequence of any treatment changes. Nevertheless, our multiple regression analysis identified to be a powerful independent factor influencing the relationship between brachial and central aortic pressures, with the latter being higher at lower s. Clinical implications. These data have important clinical implications. There is a well-recognized association between a lower and cardiovascular health reported from observational studies (36 38). This is often used as a justification for therapeutic reductions in. In the setting of symptomatic ischemic heart disease and in patients with chronic stable heart failure, lowering by beta-blockade has been shown to be a very effective treatment strategy. However, the data from the present study question whether extending these assumptions to people with hypertension, especially older people with stiff conduit arteries, is safe and appropriate. Moreover, because the effect of on central pressures seems so powerful, our data suggest that there will be less effective central aortic systolic and PP reduction in older hypertensive patients with all betablockers, or other drugs that lower. In this regard, the newer generation of vasodilating beta-blockers must be shown to be as effective as alternative treatments in preventing cardiovascular events before they can be considered as a suitable routine treatment for older people with hypertension. Conclusions In summary, the CAFE-Heart Rate study has demonstrated that a lower is associated with higher central aortic systolic and PPs in patients with treated hypertension. 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Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med 2;162: Key Words: beta-blocker y heart rate y central aortic pressure y hypertension. APPENDIX For the text on the measurement of pressure waveforms and definition of variables derived by pulse wave analysis, a list of the CAFE investigators, and a figure on the central arterial pressure wave with derived parameters, please see the online version of this article. Go to to take the CME quiz for this article.