the Baker Heart Research Institute (A.M.D., B.A.K.)
University of Melbourne (C.D.G.)
Second Australian National Blood Pressure Study Group (K.W., Y.-L.L., K.L.B., L.M.H.W., C.M.R., P.R., L.J.B., G.L.R.J., C.I.J., J.J.M., G.J.M., T.O.M., M.J.W.), LaTrobe University (J.D.C.), Melbourne, Victoria, Australia.
Abstract
Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease-free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study (untreated blood pressure 169/88±12/8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease-free survival (hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure 81 versus <81 mm Hg; P=0.01), no such relation was found for carotid augmentation index (HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance (HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.
Key Words: blood pressure elderly risk factors gender
Introduction
Cardiovascular disease remains one of the leading causes of morbidity and mortality in the Western world. Risk assessment and stratification aims to identify groups of individuals in the population with higher-than-average risk. The goal is to target preventative strategies, including drug therapy, in these higher risk groups in an attempt at providing cost-effective prevention at the population level.1
Arterial hypertension has long been known to be a major risk factor for future events, with both untreated and on-treatment blood pressure predicting future events.2eC5 It is our current understanding that hypertension exerts this deleterious effect mainly via its effects on target organs, including the heart, that is, left ventricular hypertrophy, and blood vessels, that is, accelerated atherosclerosis and atheroma formation. Not surprisingly, direct measurements of effects on target organs, (eg, the determination of left ventricular mass), better predict outcome than do measurements of blood pressure alone.6eC9
Numerous techniques have been devised to assess arterial properties and function. The simplest of these in an office setting is the measurement of pulse pressure, which depends not only on the prevailing level of mean arterial pressure, but also on the elasticity of the central blood vessels. Again, pulse pressure predicts outcome in the middle aged and elderly.10,11 The assessment of aortic stiffness by measurement of pulse wave velocity in certain populations had been encouraging.12eC16 Over the last decade, more elaborate and, hence, labor-intense techniques have been devised to more accurately define vascular properties. To be valuable as a risk stratification tool, they would need to justify the additional effort.1 Initial application in extremely high-risk populations has been particularly positive.14 However, the question remains as to the additional value conferred by these techniques in a more general, hypertensive population in whom, at least among older subjects, the case for pharmacological treatment is already strong.
We prospectively measured brachial blood pressure, central systolic pressure, carotid augmentation index (AI), time to the augmentation point, and systemic arterial compliance (SAC) in a subset of participants in a randomized, controlled trial of treatment of arterial hypertension in the elderly (The Australian National Blood Pressure Study 2 [ANBP2]).17 We compared the ability of each measurement in predicting outcome by determining the hazard ratio (HR) for subsequent events of female participants in the top half of values versus the lower half.
Methods
ANBP2 recruited older (65 to 84 years) hypertensive patients from family medical practices, with the use of a prospective, randomized (diuretic or angiotensin-converting enzyme inhibitor), open-label design, with blinded assessments of end points.17 Dedicated study nurses measured brachial blood pressure by sphygmomanometry performed with the subject seated after 5 minutes of rest and using Korotkoff sounds I and V. The randomization blood pressures presented in this article were the average of 3 measurements taken on 2 occasions, 1 week apart, and after withdrawal of any antihypertensive medication where applicable. After ascertaining eligibility, but before randomization, participants recruited in the greater Melbourne area were asked to participate in a substudy on left ventricular and arterial properties. Prior separate ethics approval for the substudy and use of associated trial data were obtained from the Ethics Committee of the Royal Australasian College of General Practitioners, which had also approved the main ANBP2 trial.
Arterial waveforms were obtained with participants recumbent in a quiet air-conditioned room. After 10 minutes of rest, a carotid pressure waveform was obtained by applanation tonometry of the proximal right carotid artery using a pencil-type transducer (Micro-tip SPT-301, Millar Instruments). Blood flow was measured simultaneously with a continuous wave 4.0 MHz zero-crossing Doppler velocimeter in the suprasternal notch directed at the ascending aorta (Multi Dopplex MD1, Huntleigh Technology). Brachial blood pressure was measured with a Dinamap 1846 SXP (Critikon) in triplicate, and the means of these values were used for subsequent calculations.18 From the waveform recordings, 3 and a maximum of 10 representative cardiac cycles were selected by a single operator (K.L.B.), and the parameters obtained from each waveform were averaged. Waveforms were linear detrended assuming equality at the start and end of each cardiac cycle and scaled to brachial diastolic and mean pressure. Other than selection of representative waveforms, all of the analysis was fully automated.
On the carotid waveforms obtained by tonometry, we identified the augmentation point from the first zero crossing from positive to negative of the fourth derivative occurring 50 ms after the foot of the waveform.19 Augmented pressure was determined as the difference between the pressure at the augmentation point and peak systolic pressure, with AI as the ratio between this and the pulse pressure in that particular cardiac cycle.
Immediately afterward, 2D-guided M-mode echocardiography of the aortic root was performed as described previously using Hewlett-Packard Sonos 500 equipment and recorded on videotape.20eC22 SAC was determined from the same averaged cardiac cycles using measurements of both pressure and Doppler flow of the ascending aorta using aortic diameter measurements of the aortic root.20 The repeatability over 2 to 4 weeks of SAC, AI, and aortic distensibility have been reported previously, including Bland-Altman plots of the data.23,24
End points were as defined in the main study.17 Cause-specific cardiovascular events included the following: coronary events, including myocardial infarction, sudden or rapid death from cardiac causes, other deaths from coronary causes, or coronary events associated with therapeutic procedures involving the coronary arteries; other cardiovascular events, including heart failure, acute occlusion of a major feeding artery in any vascular bed other than cerebral or coronary, death from noncoronary cardiac causes, dissecting or ruptured aortic aneurysm, or death from vascular causes; and cerebrovascular events, including stroke and transient ischemic attacks. Participants were followed for a median of 4.1 years from the time of randomization. The main trial demonstrated a significant effect of treatment with an angiotensin-converting enzyme inhibitor on mortality, particularly evident in men, whereas in women both treatments were found equal (HR, 1.00; 95% CI, 0.83 to 1.21). Concomitant medication (sometimes in combination) included calcium channel blockers (23.9%), adrenoceptor blockers (12.2%), and angiotensin receptor blockers (13.1%). Given the considerable, largely anatomically determined differences in arterial properties between men and women, the different mortality between men and women, and the effects of treatment, the substudy was only powered to answer the question in women, where both randomized treatment groups could be combined for analysis. Preliminary analyses in the male subgroups indicated that neither brachial systolic nor pulse pressures were predictive of outcome, in contrast with the results presented here for women.
All of the group data are presented as mean±SD after list-wise deletion of cases with missing data except where indicated otherwise. The relative dispersion of measures was assessed by comparing their coefficients of variation (cv) (SD/meanx100%). Comparisons between means were evaluated by unpaired Student t test. Multiple regression used a method of stepped entry (P<0.05) and removal (P<0.10). To compare the predictive ability of baseline measures with different units (ie, blood pressure, AI, and SAC), events rates (death or first defined cardiovascular event) per 1000 patient years of follow-up were related to dichotomized values of each baseline measure using a Cox regression method and HRs (and corresponding 95% CIs) calculated for these.3
Results
The baseline characteristics of the entire female ANBP2 cohort and the 484 participants in the current substudy are shown in Table 1. There were no significant differences between the entire ANBP2 and the current substudy in any of the parameters measured in both. The prevalence of reported vascular disease (any of symptomatic coronary, cerebral, or peripheral) was low (7%). Expectedly, automated blood pressure taken during recumbency was significantly lower by 4/7±18/10 mm Hg (P<0.001/0.001) than randomization blood pressure.
Multiple regression analysis for AI and SAC was performed to determine whether the central arterial waveform measurements relate to its known underlying determinants as expected. The following regression equations were obtained yielding an r of 0.39 for AI (P<0.001) and 0.46 for SAC (P<0.001): equation
where CR is heart rate, H is body height, and MAP is mean arterial pressure. These results are consistent with expectations from previously published studies.
Hemodynamic and waveform variables obtained at baseline were examined for their ability to predict cardiovascular disease-free survival. To facilitate comparison between different variables, the cohort was dichotomized by the median value for each predictor variable, and the HR associated with being a member of the cohort with the higher values was calculated. HRs are presented for unadjusted outcome data (Figure) and also for data adjusted for age, cholesterol, and cigarette smoking (Table 2). For the unadjusted data (Figure) both systolic and pulse pressures obtained manually at randomization and at the time of arterial waveform assessment by automated oscillometry predicted differences in cardiovascular disease-free survival. Thus, the event rate was 35.8 per 1000 person-years for those with baseline oscillometrically determined systolic pressures above the median but only 18.3 for those with pressures below the median. Brachial systolic and pulse pressures also predicted cardiovascular disease-free survival when analyzed per 10 mm Hg difference in pressure with HRs of 1.19 (95% CI, 1.05 to 1.35; P=0.010) and 1.29 (95% CI, 1.09 to 1.54; P=0.003), respectively. In contrast with systolic and pulse pressures, neither diastolic nor mean pressures were predictive of outcome in this cohort (Figure). When adjusted for other determinants of outcome (age, cholesterol, and cigarette smoking), randomization systolic and oscillometric systolic and pulse pressures remained predictive of cardiovascular disease-free survival (Table 2). With such adjustment, randomization systolic blood pressure was no longer a significant predictor (P=0.09).
Cardiovascular disease-free survival among female participants in relation to baseline measurements. HR of occurrence of events in subjects being in the higher half of each measurement at baseline vs subjects in the lower half and 95% CIs. SBP indicates systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure. In parentheses, actual median value in cohort used to divide between higher and lower half.
Although there was a tendency toward fewer events with an increased AI and an increased compliance, neither AI nor SAC predicted outcome significantly (Figure). Similarly time to augmentation point (Figure) failed to predict outcome, and this was also the case if time to augmentation point was adjusted for height (data not shown). Baseline AI in participants without events was 38±12% and in those with events was 37±10% (P value not significant; Table 3). Respective values for SAC were 0.20±0.12 and 0.18±0.07 (P value not significant). The dispersion of values within this cohort was greater for AI (cv 30.2%) than for systolic blood pressure (cv 7.3% and 13.2% for randomization and oscillometric, respectively) and pulse pressures (18.6 and 21.4%).
Discussion
The principal new finding from this study was that, although brachial pressures, regardless of whether determined manually by sphygmomanometry or automatically by Dinamap, were related to clinical outcome in older hypertensive women, measures derived from the central arterial waveform were not, at least not significantly so. This is the first examination in a predominantly asymptomatic population of hypertensive participants of the predictive value of these measures in an outcome study. Although given the nature of the cohort, namely elderly and hypertensive, a negative outcome could have been anticipated for the reasons subsequently discussed in detail, this demonstration is of relevance given the increasing interest in such measures for risk prediction. It is important to clearly establish who may and who may not derive prognostic information from such additional investigation.
Baseline determinants of AI and SAC showed excellent agreement with previous findings, suggesting that the method by which either AI or SAC were determined was sufficiently accurate to demonstrate those (expected and known) differences. AI was greater and SAC smaller with increase in mean arterial pressure.25eC27 AI was less with greater height and heart rate, whereas SAC was increased with body height.26,27 These associations are consistent with the positive relation between arterial stiffness and distending pressure, the dependence of arterial compliance on body size, and of AI on the path length to major reflecting sites relative to the timing of cardiac ejection. Waveform analyses included both a parameter, which was only related to the arterial waveform and required no pressure calibration or consideration of flow (ie, AI), as well as a measure requiring both central pressure and flow measurements (SAC). To compare the predictive ability of baseline measures with different units (ie, blood pressure, SAC, and AI), and to ensure an adequate number of events per fraction, event rates were related to dichotomized values for each of the baseline measures.
A number of studies have demonstrated a relationship between measures of AI and other cardiovascular risk factors,28 and an association with the severity of coronary disease has been reported, at least in younger subjects, in some29 but not all30 studies. In male subjects, central pressures were found to better correlate with the extent of angiographic coronary disease than were brachial pressures.31 However, as demonstrated in our study, this does not necessarily mean that such measurements are helpful in a prospective setting. A previous study has demonstrated that AI and pulse wave velocity are related to cardiovascular mortality in an extremely high-risk group of patients on hemodialysis.16 An invasive study in male subjects undergoing cardiac catheterization for presumed coronary artery disease related intra-aortic AI to outcome.32 It may be that in our cohort with a low prevalence (7%) of known vascular disease, other factors including hypertension become more relevant in determining outcome than vascular stiffness. Another possibility in those on hemodialysis is the presence of an arteriovenous fistula, which has been shown to alter arterial hemodynamics, and it could be possible that AI measures other factors in addition to central arterial wave reflection in participants with such a large arteriovenous fistula.16 The lack of prognostic information from the measurement of AI could not be attributed to the absence of variation in this measure within the cohort, because the dispersion of values was actually greater for AI than for those blood pressures that were predictive of outcome. However, the relative contributions of biological variation and of measurement imprecision to this variability are not known.
The likely mechanism by which indices of arterial stiffness and cardiovascular risk factors are related is that such stiffness is increased in the presence of coronary disease,21,33,34 probably because of the often common occurrence of atherosclerosis in the coronary arteries and aorta.35 A recent study estimating central AI found this to be higher in younger participants with coronary artery disease than controls, but there was no difference in participants >60 years of age (21% and 22% respectively),29 in keeping with the present negative findings for carotid augmentation as a predictor of mortality. The lack of discrimination at older ages could reflect the fact that aging promotes near maximal stiffening of the large arteries independent of disease severity, although aortofemoral pulse wave velocity (PWV) has been found to be informative in an older population.36,37 Furthermore, aortic stiffening in the elderly minimizes the difference between central and peripheral systolic blood pressure. Thus, brachial systolic blood pressure becomes a better surrogate of central systolic blood pressure in older age groups. This fact, combined with the relative simplicity and reproducibility of sphygmomanometric brachial blood pressure measurement compared with indices of large artery stiffness, likely contributes to the greater predictive value of brachial systolic blood pressure. This is true even for oscillometrically determined pressures, which have been shown to be a major limitation in the noninvasive determination of central pressures.38
In contrast to our negative findings for measures dependent on waveform analysis, previous studies have suggested that aortic pulse wave velocity is predictive of mortality in a hypertensive cohort.12 Although differences in study populations, particularly age, may account for the conflicting findings, an additional possibility may lie in differences in methodology. Central waveforms will be dependent not only on aortic stiffness (which is the principal determinant of pulse wave velocity) but also on peripheral wave reflection. Thus, measures that predominantly depend on aortic properties, such as pulse wave velocity, may be expected to be more informative.
There are several limitations of our study. We have limited the analysis to women to combine treatment groups without losing statistical power. Even with combined groups, the number of events was small (53), which could have permitted a type 2 error with regard to some of the parameters; however, despite this, several brachial pressure measurements were related to prognosis, whereas central pressure measurements AI and SAC were not. Our results may not be applicable to men who have comprised the majority of subjects in previous studies relating large artery properties to coronary disease. Our cohort had a low prevalence of vascular disease and were all aged 65 to 84 years. The predictive value of the indices measured may have been different in a younger cohort, in whom central-peripheral hemodynamic differences would be more evident, or one with a high prevalence of vascular disease.
We did not measure aortofemoral PWV as a method to assess aortic stiffness, although time to the augmentation point (both unadjusted and adjusted for height), which will be at least partly dependent on PWV, was also not predictive of subsequent events. The comparatively short median time to augmentation point is compatible with the anthropometric and clinical characteristics of the cohort studied with short distances to the major reflecting sites and increased PWV attributed to concomitant age and hypertension. Our central arterial waveforms were carotid rather than intra-aortic, although pressure differences between these sites are small. Despite these limitations, our results indicate a substantial patient group in whom several measures of large artery behavior, including AI, are not informative of outcome.
Two large, collaborative studies39,40 have reported that mean arterial pressure is superior to pulse pressure as a prognostic hemodynamic measure. In contrast, in the current study, neither derived nor measured (oscillometry) mean pressure was predictive of outcome, whereas both systolic and pulse pressures were. This may relate to our particular cohort, although several other studies have also found pulse pressure to be a valuable predictor.11,41eC44
We conclude from the results of our study that, contrary to blood pressure measurements, the currently available arterial waveform analysis is not likely to be clinically useful in the evaluation of the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.
Acknowledgments
This study was supported by the Australian Commonwealth Department of Health and Aging; the National Health and Medical Research Council of Australia; and Merck Sharp and Dohme Pty Ltd, Australia.
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