CLINICAL RESEARCH: ARTERIAL REFLECTIONS AND STIFFNESS
Increased Wave Reflection Rather Than Central Arterial Stiffness Is the Main Determinant of Raised Pulse Pressure in Women and Relates to Mismatch in Arterial DimensionsA Twin Study
Marina Cecelja, BSc*,
Benyu Jiang, PhD*,
Karen McNeill*,
Bernet Kato, PhD ,
James Ritter, PhD*,
Tim Spector, MD and
Phil Chowienczyk, BSc*,*
* King's College London, Cardiovascular Division, London, United Kingdom
Department of Twin Research and Genetic Epidemiology, London, United Kingdom
Manuscript received October 31, 2008;
revised manuscript received April 6, 2009,
accepted April 14, 2009.
* Reprint requests and correspondence: Dr. Phil Chowienczyk, Department of Clinical Pharmacology, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom (Email: phil.chowienczyk{at}kcl.ac.uk).
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Abstract
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Objectives: Our aim was to examine the relative contributions of the first systolic shoulder (P1) and augmentation pressure ( Paug) to central pulse pressure (cPP), their relation to central arterial stiffness (pulse wave velocity [PWV]) and arterial diameters, and their respective heritability estimates.
Background: cPP is augmented above P1 by Paug due to pressure waves reflected from the periphery of the circulation.
Methods: Women (n = 496) from the Twins UK adult twin registry (112 monozygotic, 135 dizygotic pairs) age 21 to 81 years were studied. cPP, P1, and Paug were estimated using the SphygmoCor system (Atcor, West Ryde, Australia) from transformed radial waveforms. Carotid-femoral PWV was measured using the same system. Aortic and femoral artery diameters were measured by ultrasonography. Heritability was estimated using structural equation modeling.
Results: P1 and Paug accounted for 22% and 76%, respectively, of the variance in cPP. After adjustment for mean arterial pressure and heart rate, P1 strongly independently positively correlated with PWV (standardized regression coefficient, β = 0.4, p < 0.0001), whereas Paug did not independently correlate with PWV but independently negatively correlated with the ratio of the diameter of the femoral to that of the abdominal aorta (β = –0.12, p < 0.001). Estimates of heritability (h2) of cPP, PWV, P1, and Paug were 0.43, 0.34, 0.31, and 0.62, respectively, after adjustment for mean arterial pressure and heart rate.
Conclusions: These results suggest that, in women, Paug is highly heritable, is associated with the ratio of distal to proximal arterial diameters, and, independent of PWV, is a major determinant of cPP.
Key Words: central pulse pressure • arterial stiffness • wave reflection • augmentation pressure • aortic diameter
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Abbreviations and Acronyms
| | AIx = augmentation index | | cPP = central pulse pressure | | CVD = cardiovascular disease | | DZ = dizygotic | | HR = heart rate | | ISH = isolated systolic hypertension | | MAP = mean arterial pressure | | MZ = monozygotic | | PP = pulse pressure | | pPP = peripheral pulse pressure | | PWV = pulse wave velocity | | P1 = height of first systolic shoulder | | SV = stroke volume | | T1 = time of arrival of the reflected wave | | Paug
= augmentation pressure |
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Pulse pressure (PP) is a major determinant of cardiovascular risk. In older subjects, peripheral pulse pressure (pPP) measured at the brachial artery is more closely associated with future cardiovascular disease (CVD) events than systolic or diastolic pressure (1–4) and, in middle-age to older subjects, is greater in women compared with men (5). Central pulse pressure (cPP) measured at the aortic root may be a more important determinant of CVD risk than pPP, possibly as a result of the pulsatile stress imposed on the coronary arteries, myocardium, and cerebral vasculature (6). An outcome study in which cPP was measured invasively supports this hypothesis (7) as do most, but not all, studies employing noninvasive estimates of cPP (8–11). In younger subjects, amplification of pPP above cPP by effects of reflection in the upper limb (12) may reduce the association of pPP with CVD events (13). cPP is, in part, determined by the stiffness of central arteries but is also thought to be influenced by left ventricular ejection stroke volume (SV), heart rate (HR), and pressure wave reflection (14). cPP can be separated into 2 components: the height, above diastolic pressure, of the first systolic shoulder in the arterial pulse waveform (P1), and augmentation pressure (Paug), the height of central systolic pressure above P1 (Fig. 1) (12,15,16):
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Figure 1 Aortic and Peripheral Pressure Waveforms
Aortic and peripheral pressure waveforms showing central systolic pressure (cSBP), peripheral systolic pressure (pSBP), central pulse pressure (cPP), and peripheral pulse pressure (pPP). cPP can be divided into 2 components: the height of the first systolic shoulder (P1) above diastolic blood pressure (DBP) (equal at central and peripheral sites) and augmentation pressure (Paug), thought to be determined by wave reflection. T1, the time of the first systolic shoulder, is thought to be determined by the time of arrival of the reflected wave.
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cPP = P1 + Paug
These components of cPP may be differentially related to arterial stiffness and wave reflection, with P1 formed by the outgoing pressure wave and dependent on SV and arterial stiffness via a "Windkessel" effect and Paug determined mainly by pressure wave reflection and, hence, on the serial distribution of arterial dimensions and stiffness. The purpose of the present study was to examine the relationship of PP and its components to SV, arterial stiffness, and large artery dimensions, and second, to determine the heritability of PP, arterial stiffness, and arterial dimensions. To do this, we studied a sample of women age 21 to 81 years from the Twins UK cohort.
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Methods
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Subjects comprised 496 unselected female Caucasian twins, 112 pairs of monozygotic (MZ) and 135 pairs of dizygotic (DZ) twins age 21 to 81 years, with a mean age of 58 years. Ninety-one (18.3%) of these were on treatment with antihypertensive drugs, and 58 (11.7%) were on lipid-lowering treatment. Subject characteristics are summarized in Table 1. The study was approved by the St. Thomas' Hospital Research Ethics Committee, and written informed consent was obtained from all subjects. Measurements were performed during a single visit to a quiet temperature-controlled vascular laboratory (22°C to 24°C).
Hemodynamic measurements.
Brachial blood pressure was measured in duplicate, using a validated oscillometric device (Omron 705CP, Omron, Tokyo, Japan), after subjects had been seated in a quiet room for at least 10 min. Radial pulse waveforms and measurements of central arterial stiffness (carotid-femoral pulse wave velocity [PWV]) were obtained with the subject in a supine position using the SphygmoCor system (Atcor, West Ryde, Australia). Applanation tonometry of the radial artery with a high-fidelity transducer (Millar Instruments, Houston, Texas) was used to obtain an ensemble averaged radial pulse. The radial artery pressure waveform was calibrated to supine brachial blood pressure. The inbuilt transfer function in the SphygmoCor system provided a corresponding aortic pulse waveform from which cPP, P1, Paug, and central systolic blood pressure were identified (16). Carotid-femoral PWV was calculated from sequential recordings of electrocardiogram-referenced carotid and femoral pressure waveforms obtained by tonometry using the same device and transducer. The path distance between the carotid and femoral sites was estimated from the distance between the sternal notch and femoral artery at the point of applanation. This reduces errors introduced by multiple measurements and is closer to the true path length than the carotid to femoral distance (17). PWV and cPP measurements were made in triplicate, and mean values were used for analysis. Only waveforms that passed the automatic quality control criteria of the SphygmoCor system were used.
Ultrasonography of the aortic root, abdominal aorta, and femoral arteries.
The aortic root was visualized using 2-dimensional echocardiography from a long-axis parasternal view using a Siemens CV70 with a 4-MHz cardiac transducer, and its diameter measured 1 cm from the aortic valve between the anterior and posterior aortic root wall at end diastole. SV was measured in a subgroup of 186 subjects. The cross-sectional area of the aortic valve was estimated from diameter measurements and SV determined by multiplying the cross-sectional area by the velocity time integral obtained from Doppler flow velocity at the level of the aortic valve. To visualize the abdominal aorta, the epigastrium was scanned vertically at the xiphoid process using the same probe. The diameter of the abdominal aorta was measured 1 to 2 cm below the diaphragm at end-diastole. Left and right femoral arteries were visualized with a 13-MHz vascular probe 1 cm proximal to the bifurcation. Automated wall tracking software (Medical Imaging Applications, Coralville, Iowa) was used to measure diameter at end-diastole.
Statistical analysis.
Data analysis was performed with SPSS version 14.0 (SPSS Inc., Chicago, Illinois). Genetic modeling was performed using Mx software (Mx statistical modeling, Medical College of Virginia, Richmond, Virginia). Subject characteristics are presented as mean ± SD unless otherwise stated. Student unpaired t and chi-square tests were used to test for differences in characteristics between MZ and DZ twins. Univariate regression analysis was first used to examine relationships of cPP, pPP, P1, and Paug as dependent variables to PWV, mean arterial pressure (MAP), HR, arterial diameters, and potential confounding factors: age, height, weight, smoking status, total cholesterol, high-density lipoprotein cholesterol, and the presence of diabetes. Forward stepwise multiple regression analysis was then performed to examine potential independent determinants of cPP, pPP, P1, and Paug. Variables included in each analysis were age, HR, MAP, PWV, arterial dimensions (aortic root diameter, abdominal aortic diameter, the ratio of femoral to abdominal aortic diameter), and any other confounding variables found to significantly correlate with the dependent variable in the initial univariate analysis. The same analysis was also applied to the time of arrival of the reflected wave (T1) (Fig. 1). The analysis was repeated separately in women age <60 and  60 years, because the prognostic importance of PP changes at approximately 60 years in women (1), and age category (<60 and 60 years) interactions with variables entering the final model were tested. All statistical tests were done at the 5% level of significance.
Heritability analysis was performed using the classical twin model in which a greater similarity in MZ compared with DZ twins suggests a genetic influence, based on the fact that MZ twins are genetically 100% identical and DZ twins share approximately 50% of their segregating genes. This model assumes that MZ and DZ twins share their common environment to the same extent. Twin resemblance for each of the phenotypes was examined using the intraclass correlation coefficient for each zygocity. A higher intraclass correlation coefficient for MZ twins compared with DZ twins suggests a genetic influence on the phenotype. For further analysis of genetic and environmental contributions, the variance of each phenotype was assumed to derive from an additive genetic component (sum of individual effects of all loci that influence the trait), shared or unique environment components (ACE model). Measurement error is represented under unique environmental influences. Structural equation modeling implemented in Mx was used to estimate the parameters of the ACE model and corresponding confidence intervals.
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Results
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Characteristics of the MZ and DZ female twins were similar, but there were small but significant differences between MZ and DZ twins in the separate age groups (Table 1). Mean age and peripheral systolic blood pressure were significantly lower in MZ compared with DZ twins age <60 years. More subjects were on antihypertensive treatment in MZ twins age 60 years compared with DZ twins in the same age group.
Relationship of pPP and cPP to PWV and arterial dimensions.
Mean cPP was less than pPP by 9 and 7 mm Hg in subjects age <60 and 60 years, respectively (each p < 0.001). Both cPP and pPP correlated with MAP, HR, age, PWV, high-density lipoprotein cholesterol, aortic root diameter, and smoking but not with height or weight by univariate analysis. However, in multiple regression analysis including all variables correlated with PP on univariate analysis, the only significant correlations were with MAP, HR, age, and PWV (each p < 0.0001) (Table 2).
Contribution of P1 and Paug to cPP.
Mean values of P1 were greater than those of Paug for subjects in each age group and in each tertile of the distribution of cPP (Fig. 2). However, Paug contributed proportionately more to the increase in cPP across the distribution than P1. Thus, in the whole cohort, P1 increased by a mean of 12.0 mm Hg (52% increase) when comparing women in the first and third tertiles of cPP but Paug increased by 14.1 mm Hg (196% increase). In women meeting a definition of isolated systolic hypertension (ISH) with peripheral systolic blood pressure >140 mm Hg and diastolic blood pressure <90 mm Hg, P1 was 37.5 compared with 26.7 mm Hg in women without ISH. Corresponding values of Paug were 21.6 and 12.7 mm Hg in women with and without ISH, respectively. In regression analysis (including Paug and P1 as predictors of cPP), Paug and P1 explained 76% and 22% of the variance in cPP. In women age <60 years, this was 73% and 24%, respectively, and in women age 60 years was 76% and 21%, respectively.
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Figure 2 Central Pulse Pressure
Mean values of P1 and augmentation pressure in relation to central pulse pressure in women <60 and 60 years of age. P1 = height of first systolic shoulder.
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Relationship of P1 and Paug to PWV and arterial dimensions.
In multiple regression analysis (incorporating all variables significantly correlated with P1 on univariate analysis), in the whole cohort and in each age group, P1 strongly positively correlated with PWV and MAP but less strongly correlated with HR, arterial diameters, and other variables (Table 3). There were significant interactions between age category and MAP and between age category and HR.
Paug strongly positively correlated with MAP and age and negatively correlated with HR. Paug did not significantly correlate with PWV. T1 did not independently correlate with PWV but independently correlated (standardized regression coefficient, β = 0.23, p < 0.001) with the ratio of femoral to abdominal aortic diameter. T1 also significantly correlated with height and (negatively) with MAP. There were significant interactions between age category and HR and between age category and the ratio of femoral to abdominal aortic diameter. In subjects age <60 years (as in the whole cohort) but not in subjects age 60 years, Paug negatively correlated with the ratio of femoral to abdominal aortic diameter. In the subsample of subjects in whom SV was assessed (Table 4), SV was weakly or nonsignificantly related to P1 and Paug, and the main findings with respect to correlations with PWV were unaltered: P1 remained strongly correlated with PWV, whereas Paug did not significantly correlate with PWV. The strength of the correlation between Paug and the ratio of femoral to abdominal aortic diameter in subjects age <60 years was stronger, but that of P1 to the ratio of femoral to abdominal aortic diameter was no longer significant.
Heritability analysis.
Intraclass correlations for all measures were greater for MZ compared with DZ twin pairs (Table 5), indicating a genetic influence on all phenotypic traits. Heritability estimates are shown in Table 6. In the full ACE model, heritability of PWV was modest, with an estimated genetic component of 34%. The estimated genetic components of cPP, P1, and Paug were 43%, 31%, and 62%, respectively. Heritability of Paug was reduced to 43% when corrected for height in addition to HR and MAP. PWV was the only measure for which shared environment was significant.
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Discussion
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PP and PWV.
PP is often regarded as a surrogate for PWV, ejection of blood into a stiff aorta resulting in a high systolic and pulse pressure. A correlation between PP (both peripheral and central) and carotid-femoral PWV is a universal finding in large epidemiological studies (18–22), but much of the variation in PP is not explained by PWV or other measures of central artery stiffness (18–22). Other factors invoked to explain PP include left ventricular ejection volume, pressure wave reflection, and arterial diameters (23). As in the present study, previous studies have found only a weak relation between left ventricular ejection volume and PP (20,21).
Contribution of P1 and Paug to cPP.
To our knowledge, this is the first study to examine separately the contribution of the 2 major components of PP, P1 and Paug, to cPP. Although P1, the component of PP generated by the outgoing pressure wave, was greater than Paug, the variance of Paug was greater than that of P1. Thus, most of the variability in cPP (and in pPP) was accounted for by variation in Paug rather than P1. Partitioning of cPP into Paug and P1 provides physiological insight into the mechanisms governing cPP. P1, the outgoing component of the pressure wave, might be expected to be mainly determined by PWV, which determines the Windkessel function of the central vessels. By contrast, arterial geometry might be expected to influence pressure wave reflection more strongly than arterial stiffness (although stiffness could also influence this through earlier return of reflected waves). In the present study, we found that P1 indeed highly correlated with PWV. However, Paug did not independently correlate with carotid-femoral PWV. This suggests that PWV is not a major determinant of Paug and is consistent with other studies showing dissociation between measures of pressure wave reflection and PWV during interventions that influence vasomotor tone (24,25).
Our findings differ from those of Mitchell et al. (26) in the Framingham offspring cohort of men and women, where although Paug (obtained from carotid tonometry) was seen to account for a considerable proportion of variance in cPP, PWV accounted for a greater proportion of the variance in cPP than Paug. However, subjects with hypertension (47% of the potential study population) were excluded. The present study shows that Paug positively correlated with MAP and so would be expected to provide a greater contribution to cPP in subjects representative of the general population, including those with hypertension. The conclusions of our study also differ from those of Segers et al. (27) who examined wave reflection in middle-age men and women and found wave reflection to explain at most 26% of the variance in carotid PP. Segers et al. (27) used the augmentation index (AIx) (equal to Paug/cPP) as a measure of reflection in their regression models, which also included measures of input impedance. The proportion of variance in cPP explained by AIx compared with Paug will be reduced by cPP being itself a denominator of AIx. Our simple approach, where we have portioned cPP into the sum of P1 + Paug, provides less insight into impedance but provides an estimation of the relative contributions of P1 and Paug, which is limited only by the accuracy of the measurements.
Physiological and structural determinants of P1 and Paug.
Both P1 and Paug could be influenced by arterial geometry. For a given intrinsic elasticity of the aortic wall (to which PWV is related by the Moens-Korteweg equation [28]), the functional compliance of the aorta is directly related to its diameter (29). Although this is offset by the fact that SV and HR are related to body size and aortic root area, P1 might be expected to be inversely related to aortic diameters, particularly those beyond the aortic root. However, one hypothesis of age-related stiffening is that elastin degeneration is associated with aortic dilation (30), and this might blunt or over-ride the expected inverse relation. In the present study, we found a weakly positive correlation of P1 with abdominal aortic diameter in subjects <60 years of age, a negative correlation in subjects 60 years of age, and no significant relation in the overall cohort. This result is consistent with recent studies that have found a modest inverse correlation of cPP with aortic root diameter in older women (20,21).
Wave reflections are thought to occur at discontinuities in impedance and thus to depend on the serial distribution of arterial diameter and elasticity, with most reflection arising distal to the aortic bifurcation. In the present study we measured abdominal aortic diameter as a measure of proximal artery dimensions and femoral artery diameter as a measure of distal arterial dimensions. Of all arterial dimensions, Paug was best predicted by the ratio of femoral to abdominal aorta diameter, with an inverse relationship between Paug and femoral/aortic diameter. This is consistent with the amount and/or timing of reflection being determined by the mismatch between femoral and aortic dimensions or between other distal and proximal arterial dimension, with femoral and aortic dimensions acting as a surrogate for these. The highly significant independent association of T1, the time of arrival of the reflected wave, with femoral/aortic diameter suggests that arterial dimensions have a greater influence on the site of reflection than on the amount of reflection. Furthermore, the lack of association of T1 with PWV suggests that it is primarily the site of reflection that determines the time of arrival of reflected waves and over-rides the importance of transit time to and from the site of reflection. The association between Paug and femoral/aortic diameter was driven by subjects <60 years of age. In subjects 60 years of age, in whom PWV is higher, it may be that serial distribution of elasticity becomes more important than that of diameter. Further studies including prospective studies will be required to explore the complex relation between Paug and arterial diameter.
Heritability of P1 and Paug.
To our knowledge, this is the first study to report heritability of the different components of cPP, P1, and Paug in twins. Heritability of P1 (31%) was modest as was that of PWV (34%), consistent with P1 being determined in large part by PWV. The estimate for PWV is consistent with previous estimates of the heritability of PWV from family and twin studies between 0.26 and 0.40 (31,32). The heritability of Paug (62%) is greater than that observed for most phenotypic traits including systolic blood pressure, and suggests that if other factors such as measurement error are similar, factors additional to PWV that determine reflection have a high genetic component. The findings with respect to Paug are similar to those of AIx, which is known to be highly heritable (33). Although our estimates of the heritability of aortic dimensions were relatively low, these estimates were relatively crude measures of the detailed geometry that determines wave reflection. The high heritability of Paug could be explained by high heritability of detailed arterial geometry, which is, in turn, determined by intrinsic geometry and smooth muscle tone.
Implications for systolic hypertension in women.
The finding that Paug accounts for the majority of the variation in cPP and that it is highly heritable and independent of PWV has a number of important implications for systolic hypertension in women. It challenges the view that systolic hypertension arises primarily from irreversible stiffening of the aorta caused, for example, by collagen cross-linking and/or calcification. It raises the potential importance of Paug as a risk factor in addition to the well-established risk associated with elevated PWV in hypertension (6,34). It suggests that drugs with a specific action to dilate muscular arteries (and therefore to increase distal/proximal dimensions and reduce wave reflection) could be effective in reducing PP and systolic pressure. Organic nitrates have such specificity for large muscular arteries (35), but their efficacy may be limited by tolerance, increase in oxidative stress, and possibly other nonhemodynamic adverse effects (36). The high heritability of Paug suggests that Paug is an important trait to examine in relation to potential genes involved in hypertension and CVD.
Study limitations.
The study was limited to female twins. The results are likely to be representative of women in the general population, since characteristics and CVD risk profiles of the Twins UK cohort are similar to that of the general population (37), and the mortality of twins is similar to that of the general population (38). The results cannot, however, be generalized to men. We estimated central arterial pressure waveforms from radial waveforms using the SphygmoCor transfer function. Most of the error inherent in this process, at least when computing cPP, is attributable to the limited accuracy with which peripheral blood pressure can be measured (16). When calibration is performed from brachial blood pressures (as in this study), the approach also ignores amplification from the brachial to the radial artery, which may lead to an overestimation of peripheral amplification (39). Although this affects absolute values of cPP and pPP, it does not affect the relative values of cPP and pPP (40) or those of Paug and P1, and thus is unlikely to affect interpretation of the study. We made limited measurements of arterial diameters and cannot exclude the possibility that other relations between Paug and arterial dimensions would emerge if dimensions of smaller arteries were available.
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Conclusions
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In a cohort of apparently healthy women age 21 to 81 years, increased wave reflection rather than PWV is the main determinant of raised PP and, especially in younger women age <60 years, may be driven by mismatch in distal-to-proximal arterial dimension. This is likely to be a useful phenotype—both clinically and for gene discovery.
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Footnotes
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This work was supported by a British Heart Foundation Project Grant PG/06/032. The Department of Twin Research receives funds from the Wellcome Trust. The authors acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust, in partnership with King's College London and King's College Hospital NHS Foundation Trust.
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The Pulse of Cardiology: Quo Vadis?
- Michael F. O'Rourke and Christopher S. Hayward
J. Am. Coll. Cardiol. 2009 54: 714-717.
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Inside This Issue
J. Am. Coll. Cardiol. 2009 54: A24.
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M. Cecelja and P. Chowienczyk
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