Published online before print May 7, 2007, doi: 10.1161/CIRCULATIONAHA.106.667733
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(Circulation. 2007;115:2628-2636.)
© 2007 American Heart Association, Inc.
Epidemiology |
Cross-Sectional Correlates of Increased Aortic Stiffness in the Community
The Framingham Heart Study
From Cardiovascular Engineering, Inc, Waltham, Mass (G.F.M.); National Heart, Lung, and Blood Institute Framingham Study, Framingham, Mass (C.G., E.J.B., M.G.L., M.J.K., R.S.V., D.L.); Department of Mathematics and Statistics, Boston University, Boston, Mass (C.G., M.G.L., M.J.K.); Evans Department of Medicine (E.J.B., J.A.V., R.S.V., D.L.), Whitaker Cardiovascular Institute (E.J.B., J.A.V., R.S.V.), and Section of Preventive Medicine (E.J.B., R.S.V.), Boston University School of Medicine, Boston, Mass; and National Heart, Lung, and Blood Institute, Bethesda, Md (D.L.).
Correspondence to Gary F. Mitchell, MD, Cardiovascular Engineering, Inc, 51 Sawyer Rd, Suite 100, Waltham, MA 02453. E-mail GaryFMitchell{at}mindspring.com
Received October 1, 2006; accepted March 20, 2007.
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Abstract |
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Background— Increased aortic stiffness is associated with numerous common diseases of aging, including heart disease, stroke, and renal disease. However, the prevalence and correlates of abnormally high aortic stiffness are incompletely understood.
Methods and Results— We evaluated 2 aortic stiffness measures, carotid-femoral pulse wave velocity and forward pressure wave amplitude, in a pooled sample of the Framingham Original, Offspring, and minority Omni cohorts (mean age, 62 years; 56% women). Abnormal stiffness of each measure was defined as a value exceeding the sex-specific 90th percentile of a reference group with a low burden of conventional cardiovascular disease risk factors. Applying this criterion to the entire sample identified a 24% to 33% prevalence of abnormal stiffness measures. The prevalence of abnormal stiffness increased markedly with age, eg, for pulse wave velocity, from a few percent in both sexes aged <50 years to 64% (men) to 74% (women) in those aged 
70 years. With adjustment for age, important correlates of abnormal aortic stiffness included higher mean arterial pressure, greater body mass index, impaired glucose metabolism, and abnormal lipids. Correlates of aortic stiffness were similar if we used age-specific rather than fixed criteria for defining abnormal stiffness.
Conclusions— The prevalence of abnormal aortic stiffness increases steeply with advancing age in the community, especially in the presence of obesity or diabetes. Our data suggest that the burden of disease attributable to aortic stiffness is likely to increase considerably over the next few years as the population ages.
Key Words: arteriosclerosis • blood pressure • hypertension • obesity • population • risk factors • vasculature
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Introduction |
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Abnormally high aortic stiffness is associated with increased risk for various adverse health outcomes, including cardiovascular disease,1–4 stroke,5,6 and renal disease.7 Aortic stiffness increases substantially with advancing age, possibly as a result of accumulation of or continual exposure to traditional vascular risk factors, such as elevated blood glucose and obesity. However, aortic stiffness also increases in relatively healthy individuals with a low burden of traditional vascular disease risk factors, suggesting a background effect of aging per se or possibly reflecting exposure to unknown or nontraditional risk factors.8 Genetic factors also contribute to variability in arterial properties.9
Many studies have evaluated correlates of various continuous measures of arterial stiffness10–14; however, we are not aware of any previous community-based studies that have evaluated the prevalence of and risk factors for abnormally high aortic stiffness when assessed categorically on the basis of thresholds established in a reference sample. In light of the disease risk associated with arterial stiffening,1–7 it is important to know both the prevalence and age distribution of abnormal aortic properties in our aging society. A better understanding of factors that contribute to development of higher values for aortic stiffness may provide a useful starting point for formulating strategies aimed at preventing or reducing aortic stiffening. Therefore, the aims of the present study were to define cut points for abnormal stiffness with the use of a reference sample free of cardiovascular disease initially, and then to evaluate the prevalence of and risk factors for increased aortic stiffness in a community-based sample.
Clinical Perspective p 2636
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Methods |
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Study Participants
The designs of the Framingham Heart Study and the Framingham Offspring Study have been detailed previously.15,16 The Omni cohort of the Framingham Heart Study was recruited by advertisement and community outreach from December 1995 to January 1998. The Omni cohort consisted of residents of Framingham, aged 40 to 75 years, who identified themselves as members of a minority group.17 Our sample for the present investigation was drawn from the Framingham Original, Offspring, and Omni cohorts. Arterial tonometry was performed routinely in participants undergoing their 26th examination cycle for the Original cohort (1999–2001), seventh examination cycle for Offspring (1998–2001), and second examination cycle for Omni (1999–2001). The Boston University Medical Center institutional review board approved the protocol, and all participants gave written informed consent. Tonometry was attempted in 304 Original, 2640 Offspring, and 392 Omni participants and was analyzable at all 4 pulse sites (brachial, radial, femoral, and carotid arteries) in 276 (91% of eligible) Original, 2253 (85% of eligible) Offspring, and 316 (81% of eligible) Omni participants. Adequate tonometry was either not attempted or not obtained at individual pulse sites in the following nonexclusive proportion of cases: brachial, 3%; radial, 3%; femoral, 10%; and carotid, 6%. To generate a reference sample, participants were excluded for 1 or more of the following nonexclusive reasons: hypertension (defined as systolic blood pressure
140 mm Hg, diastolic blood pressure 90 mm Hg, or drug treatment for hypertension; n=1654), diabetes (defined as a fasting blood glucose 126 mg/dL or treatment with insulin or oral hypoglycemic agent; n=445), treatment for dyslipidemia (n=686), cardiovascular disease (coronary heart disease, heart failure, stroke, transient ischemic attack, or intermittent claudication; n=532), current smoking (defined as smoking within 12 months before the index examination; n=405), or obesity (defined as body mass index 30 kg/m2; n=959). Of the remaining 907 eligible individuals, tonometry recordings at each of the 4 pulse recording sites (ie, the brachial, radial, femoral, and carotid arteries) were available in 833 (309 men and 524 women).
Noninvasive Hemodynamic Data Acquisition
Participants were studied in the supine position after resting 
5 minutes. Supine brachial systolic and diastolic blood pressures were obtained with the use of an oscillometric device. Arterial tonometry with simultaneous ECG was obtained from brachial, radial, femoral, and carotid arteries with the use of a commercially available tonometer (SPT-301, Millar Instruments, Houston, Tex). All recordings were performed on the right side of the body. Transit distances were assessed by body surface measurements from the suprasternal notch to each pulse recording site. Tonometry and ECG data were digitized during the primary acquisition (1000 Hz) and transferred to the core laboratory (Cardiovascular Engineering, Inc, Waltham, Mass) for analysis blinded to clinical data.
Tonometry Data Analysis
Tonometry waveforms were signal-averaged with the use of the ECG R wave as a fiducial point. Systolic and diastolic cuff pressures were used to calibrate the peak and trough of the signal-averaged brachial pressure waveform. Diastolic and integrated mean brachial pressures were used to calibrate carotid, radial, and femoral pressure tracings.18 Calibrated carotid pressure was used as a surrogate for central pressure.18 The central forward wave amplitude was defined as the difference between pressure at the waveform foot and pressure at the first systolic inflection point or peak of the carotid pressure waveform.8 Carotid-femoral pulse wave velocity (PWV) was calculated from tonometry waveforms and body surface measurements as previously described.8
We evaluated correlates of 2 related but distinct measures of aortic stiffness (PWV and forward wave amplitude) because differential changes in these measures may provide clues to the mechanism of stiffening.19 Abnormalities in PWV are largely an indication of increased aortic wall stiffness. Forward wave amplitude is closely related to aortic characteristic impedance, which shares with PWV a similar dependence on aortic wall stiffness but has a markedly (5-fold) greater dependence on aortic diameter. Forward wave amplitude represents the interaction between peak aortic flow and characteristic impedance and is therefore a sensitive indicator of the relation between pulsatile aortic flow and diameter. In addition, both PWV2–4 and forward wave20 have been shown to predict outcome in earlier prospective studies.
Statistical Analysis
Baseline characteristics were tabulated separately for men and women in the reference sample and in the entire study sample (referred to hereafter as the "broad" sample). Cut points for high PWV and forward wave amplitude were first defined as the crude 90th percentiles for the full reference sample without regard for age. We also evaluated a smoothed age-specific cut point curve defined by empirically determining the local 90th percentile in the reference sample using a centered sliding window with a width of 1 decade, evaluated at 1-year intervals. Baseline characteristics of the broad sample were tabulated separately for men and women according to whether carotid-femoral PWV or forward wave amplitude fell above or below the age-specific cut point. We then estimated and plotted the proportion of individuals in the broad sample who exceeded the crude and age-specific 90th percentiles for the reference sample. To identify correlates of increased arterial stiffness, logistic regression was performed with the use of the SAS LOGISTIC procedure.21 Centered linear and quadratic terms for age were used together as a paired variable in all models. Several variables were offered as additional covariates in the modeling by a stepwise approach with a P
0.10 inclusion criterion. Potential covariates were as follows: body mass index, heart rate, mean arterial pressure, total/high-density lipoprotein cholesterol ratio, triglycerides, fasting glucose, diabetes, presence of cardiovascular disease, presence of hypertension (systolic blood pressure >140/90 mm Hg or treated), use of lipid-lowering therapy, smoking regularly over the prior 12 months, smoking within 6 hours of the examination, racial category, and walk test status. We offered a variable for racial category (white versus nonwhite) because this pooled analysis included minorities. A walk test status variable (before or after tonometry or not done) was offered because many participants underwent a submaximal walk test either before or after the tonometry evaluation. Logistic models were repeated with both the crude and age-specific cut points to determine whether factors associated with increased arterial stiffness in the younger individuals identified by an age-specific cut point persisted in the predominantly older group identified by using the crude 90th percentile as a cut point. In secondary analyses, to determine whether arterial properties exhibited seasonal variation, a variable for season at the time of the examination also was included as a potential covariate in models that used the age-specific cut points. In addition, these models were performed with the use of backwards elimination and compared with the stepwise results. Values are presented as mean±SD except as noted. A 2-sided P<0.05 was considered significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Sample Characteristics
Characteristics of the reference and broad samples are presented in Table 1. The reference sample was younger and, by design, had a healthier risk profile than the broad sample.
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Arterial Properties in the Reference Group
The crude and age-specific 90th percentiles for carotid-femoral PWV and forward wave amplitude in the reference sample are shown in Figure 1. Carotid-femoral PWV and forward wave amplitude increased substantially with advancing age in the reference sample in both men and women. Comparison of the fixed compared with the age-specific cut point for defining high stiffness revealed a crossing point at 60 years of age, after which increasing numbers of older individuals were classified as abnormal by the fixed threshold, whereas their aortic properties fell within the 90th percentile of reference individuals of comparable age (Figure 1, vertical fill pattern). Conversely, below this crossing point there was increasing potential for younger individuals with abnormal aortic stiffness compared with healthier peers of comparable age, to be categorized as having normal aortic stiffness with the use of the fixed criterion (Figure 1, horizontal fill pattern).
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Arterial Properties in the Broad Sample
Prevalences of high stiffness in the broad sample with the use of both fixed and age-specific criteria are shown in Figure 2. When a fixed threshold was used, the prevalence of abnormal aortic stiffness increased dramatically with age in women and men for both carotid-femoral PWV and forward wave amplitude. For example, the prevalence of high carotid-femoral PWV increased from 1% in both sexes aged <50 years to 64% in men and 74% in women aged 70 years. Compared with PWV, the increase in prevalence of abnormal forward wave amplitude with advancing age was less steep when a fixed cut point was used; the prevalence rose from 6% in those aged <50 years to 50% in those aged 70 years in both sexes. For both stiffness measures, if age-specific thresholds were applied to the broad sample, the increase in prevalence of high values across age groups was not as steep (Figure 2). However, the overall prevalence of high values in the broad sample (20%) remained considerably higher than the predefined prevalence in the reference sample (10%).
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Clinical Characteristics According to Arterial Properties
Characteristics of the broad sample were tabulated according to whether aortic stiffness measures fell below or above the age-specific cut point (Tables 2 and 3
). In general, men (Table 2) and women (Table 3) with stiffer arteries had higher body mass index, mean arterial pressure, triglycerides, and fasting glucose. Except for forward wave in men, the total/high-density lipoprotein cholesterol ratio tended to be higher in those with stiff arteries. The prevalences of diabetes, cardiovascular disease, hypertension, and treatment for a lipid disorder were generally much higher in those with stiff arteries in both women and men.
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Multivariable Correlates of Increased Arterial Stiffness
Despite the marked differences in the age distribution of individuals identified as having abnormally high values for stiffness with the use of fixed versus age-specific criteria (Figure 2), associations between abnormal aortic stiffness and various vascular risk factors were similar (Tables 4 and 5). Diabetes (or higher fasting blood glucose) had consistent relations with elevated PWV in men and women, whereas body mass index had consistent relations with increased forward wave amplitude. Furthermore, diabetes was strongly associated with both stiffness measures in men, whereas increased body mass index was more consistently related to abnormal arterial stiffness in women. Higher serum triglycerides and presence of a lipid abnormality requiring treatment were associated with elevated carotid-femoral PWV in men with the use of age-specific criteria. In women, both serum triglycerides and the total/high-density lipoprotein cholesterol ratio were related to PWV with the use of the fixed cut point.
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Secondary Analyses
Backwards selection with the use of age-specific cut points resulted in models that were substantially similar to the final models obtained by stepwise selection. The season variable group was not retained in any of the models. With the use of backwards selection for the PWV model in men, lipid therapy was eliminated from the model, whereas prevalent cardiovascular disease (P=0.035) and treated hypertension (P=0.028) were retained in the model. For forward wave in men, all of the original variables, including the walk test indicator variables (P=0.013), remained in the model. In addition, smoking within 6 hours of the examination (P=0.09) remained in the model. For PWV in women, the model retained the same 6 covariates presented in Table 5 with comparable odds ratios. For forward wave in women, mean arterial pressure and body mass index remained in the model, and heart rate (P=0.014), hypertension (P=0.099), and the walk test status variable (P=0.02) were also retained in the model.
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Discussion |
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We evaluated the prevalence of increased values for 2 measures of aortic stiffness, carotid-femoral PWV and forward wave amplitude, across a wide age range in a community-based sample using fixed and age-specific cut points derived from a reference sample with a low burden of traditional cardiovascular disease risk factors. The goal of the fixed cut point analysis was to establish the overall prevalence and age distribution of abnormally high aortic stiffness in the community. Fixed cut points were set at the overall sex-specific 90th percentile for the reference sample. These same sex-specific cut points applied to the broad sample identified high PWV in 25% of the men and 33% of the women and high forward wave amplitude in 24% of the men and 26% of the women. Thus, the prevalence of increased aortic stiffness in the broad community-based sample was 2- to 3-fold higher than the prevalence in the reference sample. Furthermore, the prevalence of increased stiffness varied markedly with age, from a few percent for either stiffness variable in men and women aged <50 years to a remarkable 74% for PWV in women aged
70 years (Figure 2). If aortic stiffness contributes to cardiovascular disease risk, the steep rise in the prevalence of increased aortic stiffness with advancing age suggests that the burden of disease attributable to aortic stiffness would be expected to rise dramatically in coming years as the population ages.
To evaluate relative abnormalities in aortic stiffness at a given age, we evaluated prevalences of abnormal stiffness using age-specific cut points. Using the age-specific approach, we found increased PWV in 21% of men and 23% of women and increased forward wave amplitude in 22% of men and 20% of women, with only modest differences among age groups. These age-specific prevalences (>20%) were more than twice those found in the reference sample (10% by definition), giving an approximate indication of the substantial influence of factors other than age on arterial properties in the broad sample. Despite marked differences in the composition of groups identified as having increased aortic stiffness with the use of fixed and age-specific cut points (Figure 2), aside from age, the correlates of increased aortic stiffness were remarkably similar (Tables 4 and 5
), suggesting that the correlates of aortic stiffness that we have identified (elevated mean arterial pressure, abnormal glucose metabolism, obesity, and lipid abnormalities) were operative across the full range of ages studied.
The value of the fixed cut point that we used is affected by the proportion of older individuals in the reference sample. If a reference sample were defined with an age restriction excluding older people, lower cut points would be identified to define abnormality, and the age-related increase in prevalence would be even steeper. Such an approach borrows from past experience with what are now known to be inappropriate age-specific limits for other cardiovascular disease risk factors, such as blood pressure, and rejects entirely the controversial concept that arterial stiffening is an inevitable consequence of aging. However, it is important to acknowledge that selection of the optimal approach for defining abnormal values for arterial stiffness will require validation against longitudinally ascertained clinical end points.
We evaluated correlates of 2 related but distinct measures of aortic stiffness because differential changes in these measures may provide clues to the mechanism of stiffening. Abnormalities in PWV are largely an indication of increased aortic wall stiffness, whereas forward wave amplitude is more closely related to the balance between aortic flow and diameter and would be expected to increase if diameter is reduced or if flow increases but aortic diameter remains unchanged.19 The foregoing differences in the determinants of forward wave amplitude and PWV may underlie our observation that increased body mass index, which is associated with elevated cardiac output22 and increased pulse pressure,23 was more closely related to increased forward wave amplitude than PWV in men and women in the present study (Tables 4 and 5).
Higher mean arterial pressure was consistently related to abnormal PWV and forward wave amplitude with the use of fixed and age-specific criteria (Tables 4 and 5). Associations between mean arterial pressure and arterial stiffness are generally attributed to passive effects of increased distending pressure. However, passive distension should have a predominant effect on PWV compared with forward wave amplitude, whereas we found comparable relations between mean arterial pressure and each of the 2 aortic stiffness measures. Furthermore, prior work in the Framingham Offspring cohort24 and in other studies25 has shown that elevated pulse pressure is associated with reduced rather than increased aortic root diameter, which is not consistent with passive overdistension of the aorta. Taken together, prior literature and our present observations suggest a complexity in the relations between aortic stiffness and elevated mean arterial pressure that is unlikely to be attributable to passive distension alone.
Higher heart rate was associated with substantially increased odds for having elevated PWV in women and men. In contrast, forward wave amplitude was inversely related (men) or unrelated (women) to heart rate. The disparate relations of heart rate with PWV and forward wave amplitude underscore the importance of flow. Reduced forward wave amplitude with higher heart rate is likely a manifestation of lower stroke volume and peak systolic flow. Our finding of a direct relation between PWV and heart rate is consistent with the results of prior studies, although the mechanism of the association remains controversial.8 Regardless of the directionality of the association, increased heart rate and abnormal arterial stiffness represent important and related members of a risk factor cluster that is associated with considerable cardiovascular morbidity and mortality.
In contrast to the foregoing relations with known cardiovascular disease risk factors, in multivariable models, we found no relation between smoking, which is an established cardiovascular disease risk factor, and arterial stiffness. Prior studies have shown consistent acute increases in arterial stiffness within minutes after smoking, whereas relations between chronic smoking and arterial stiffness have been less consistent.26–28 Absent or paradoxical association between smoking and reduced arterial stiffness may relate to the much higher prevalence of smoking in younger age groups, to confounding effects of smoking on body weight, or, in the case of the present study, to the small number of smokers, which limits power to detect a relation.
The present study has several limitations. The cohort was predominantly middle-aged to elderly; therefore, our findings may not be generalizable to younger individuals. We lacked sufficient power to analyze minorities by ethnicity. Additionally, because even our reference sample is an acculturated one (in terms of a Western lifestyle), it is conceivable that healthy aging in nonacculturated samples may be associated with differing profiles of vascular stiffness measures. Furthermore, our "reference" sample was selected to be relatively low risk and free of overt disease but cannot be considered "optimal" or "healthy" in the strictest sense. Our discussion of the relative effects of wall stiffness and diameter on forward wave amplitude and PWV pertains to measurement at the same site. Because carotid-femoral PWV represents the average properties of the entire aorta and the iliac and femoral arteries, a component of any differential changes in forward wave amplitude and PWV in the presence of various risk factors may be attributable to differences in regional aortic stiffness rather than differences in local aortic diameter. The cross-sectional, observational design of the present study limits our ability to infer that the associated risk factors retained in the stepwise models caused the arterial stiffness. We cannot exclude the possibility that arterial stiffness contributed to the development of the risk factors (eg, arterial stiffness may have led to increasing mean arterial pressure and cardiovascular disease) or that the risk factors were intermediate markers of underlying causal mechanisms such as inflammation or neurohormonal activation. The present study also has several strengths, including a large sample size and routine ascertainment of coexistent cardiovascular risk factors in a multiracial sample, which provides excellent power and facilitates adjustment for multiple covariates. In addition, the community-based design reduces selection and referral biases.
In summary, we have assessed the prevalence of abnormal aortic stiffness in a community-based sample and demonstrated very high prevalences of abnormal aortic stiffness in the elderly in the presence of nominal risk factor exposure, especially elevated mean arterial pressure, abnormal glucose metabolism, increased body mass index, and abnormal lipids. We did not assess relations between arterial stiffness and events in this analysis. However, in light of known important associations between aortic stiffness and various common diseases of the elderly, our observation of a dramatic increase in the prevalence of abnormal aortic stiffness with age suggests that a considerable burden of disease in the community may be related to stiffening of the aorta. Lifestyle modification, risk factor intervention, or novel therapies that specifically target aortic stiffness may have considerable impact on the incidence of these common diseases in the elderly and commensurate impact on the overall burden of disease in our aging society. However, considerable additional work will be required to determine whether a strategy that specifically targets reduction of arterial stiffness will be superior to conventional targeting of shared risk factors for arterial stiffening and clinical events.
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Acknowledgments |
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Sources of Funding
The present study was supported by National Heart, Lung, and Blood Institute grants N01-HC-25195, HL60040, HL70100, HL71039, NO1-HV28178, and K24-HL-04334 (Dr Vasan) and by the Donald W. Reynolds Foundation.
Disclosures
Dr Mitchell is owner of Cardiovascular Engineering, Inc, a company that designs and manufactures devices that measure vascular stiffness. The company uses these devices in clinical trials that evaluate the effects of diseases and interventions on vascular stiffness. Dr Mitchell has reported receiving consulting and speaking fees from OMRON Healthcare, Inc. The remaining authors report no conflicts.
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