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(Hypertension. 1999;34:201-206.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Arterial Stiffness and the Development of Hypertension
The ARIC Study
From the Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey (D.L.); Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (D.K.A.); Departments of Epidemiology (D.L., H.A.T., G.H.) and Biostatistics (L.E.C.), University of North Carolina at Chapel Hill; Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC (W.A.R.); and Department of Epidemiology, Johns Hopkins University, Baltimore, Md (M.S.).
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Abstract |
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Abstract—Decreased elasticity in large and medium-sized arteries has been postulated to be associated with cardiovascular diseases. We prospectively examined the relation between arterial elasticity and the development of hypertension over 6 years of follow-up in a cohort of 6992 normotensive men and women aged 45 to 64 years at baseline from the biracial, population-based Atherosclerosis Risk in Communities (ARIC) Study. Arterial elasticity was measured from high-resolution B-mode ultrasound examination of the left common carotid artery as adjusted arterial diameter change (in micrometers, simultaneously adjusted for diastolic blood pressure, pulse pressure, pulse pressure squared, diastolic arterial diameter, and height), Peterson's elastic modulus (in kilopascals), Young's elastic modulus (in kilopascals), and ß stiffness index. Incident hypertension (n=551) was defined as systolic blood pressure
160 mm Hg, diastolic blood pressure 95
mm Hg, or the use of antihypertensive medication at a follow-up
examination conducted every 3 years. The age-, ethnicity-, center-,
gender-, education-, smoking-, heart rate–, and
obesity-adjusted means (SE) of baseline adjusted arterial
diameter change, Peterson's elastic modulus, Young's elastic modulus,
and ß stiffness index were 397 (5), 148 (2.0), 787 (12.7), and 11.43
(0.16), respectively, in persons who developed hypertension during
follow-up, in contrast to 407 (1), 124 (0.6), 681 (3.7), and 10.34
(0.05), respectively, for persons who did not. The similarly adjusted
cumulative incident rates of hypertension from the highest to the
lowest quartiles of arterial elasticity were 6.7%, 8.0%,
7.3%, and 9.6%, respectively, when measured by adjusted
arterial diameter change (P<0.01). One
standard deviation decrease in arterial elasticity was
associated with 15% greater risk of hypertension, independent of
established risk factors for hypertension and the level of baseline
blood pressure. These results suggest that lower arterial
elasticity is related to the development of hypertension.
Key Words: distensibility • hypertension detection and control • cohort studies • ethnic groups
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Introduction |
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Although increased arterial stiffness (decreased arterial elasticity) had been considered intrinsic to the aging process of the arterial wall,1 it has since been demonstrated that factors such as insulin resistance, smoking, and hypertension are important predictors of reduced arterial elasticity, independent of age.2 3 4 Evidence also exists to support the hypothesis that lower arterial elasticity is (directly) associated with increased risk of cardiovascular disease manifestations.2 3 5 6 A small number of population-based studies have been published describing the distribution and population correlates of arterial stiffness.2 7
This study evaluated the prospective relation between baseline arterial elasticity and the development of hypertension in a population sample. In this report, the blood pressure (BP) adjusted arterial diameter change (AADC)8 9 and conventional indices4 (Peterson's elastic modulus [Ep], Young's elastic modulus [YEM], and ß stiffness index [ß index]) were used to measure elasticity.
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Methods |
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Study Population
The sample for this study was drawn from the 15 792 individuals who participated in the baseline cohort examination of the Atherosclerosis Risk in Communities (ARIC) study. ARIC is a longitudinal study of cardiovascular and pulmonary diseases sponsored by the National Heart, Lung, and Blood Institute. It includes a community surveillance component and a cohort component. The ARIC cohort was selected as a probability sample of men and women aged 45 to 64 years at 4 study centers in the United States, 3 of which enumerated and enrolled population probability samples of the respective communities (selected Minneapolis suburbs, Minnesota; Washington County, Maryland; and Forsyth County, North Carolina). The fourth quarter of the ARIC cohort was sampled from black residents of Jackson, Miss.10 Eligible participants were interviewed and then invited to a baseline clinical examination. The baseline examination of the ARIC cohort was conducted in 1987–1989. Every 3 years after the first examination, all participants were invited to a follow-up clinical examination. The first follow-up examination was conducted in 1990–1992 and the second follow-up examination in 1993–1995. The Institutional Review Board in each participating institution approved the ARIC Study. All participants gave informed consent before each examination.
In the ARIC cohort, arterial elasticity was assessed in 11 478 participants (73% of the entire cohort), of whom 9% were assessed during the initial cohort examination and 91% during their first follow-up examination. A total of 3780 of the 11 478 participants were excluded from this analysis because they were identified as hypertensive at the time of arterial elasticity assessment. An additional 710 individuals (9% of baseline normotensives) were excluded because of missing data on hypertension status at the follow-up examinations. Thus, a final sample of 6992 baseline normotensives was available for this analysis. The follow-up time varied from 1 to 2 cohort examination cycles (3 to 6 years) depending on the time of the arterial elasticity assessment; the average follow-up time was 3.3 years. During the follow-up, 551 individuals developed hypertension, and 6441 individuals did not.
Measurement of Arterial Stiffness
The collection and evaluation of common carotid
arterial diameter and structural data in the ARIC Study
have been published extensively.4 7 8 9 11 12 13 For this
report, we used the arterial diameter data collected on the
left common carotid artery (1 cm below the origin of the carotid bulb)
during B-mode ultrasound examination of the carotid arteries. This
method uses noninvasive ultrasonic echo-tracking methods, performed by
centrally trained and certified sonographers. The data were collected
after the participants had rested in a supine position for 20
minutes. In brief, with the transducer held securely by a mechanical
transducer holder, transducer angulation was changed to maximize
media-adventitia echoes. Electronic gates were moved to track the 2
interfaces, and the distance between them as a function of time was
visualized for the consecutive cycles. These data were digitized by an
analog-to-digital converter. Then the data were sent to the ARIC
Ultrasound Reading Center, where the arterial diameter data
were estimated as the average over as many cardiac cycles as possible
(average=5.5). The reading of arterial diameter data was
performed by trained and certified ultrasound readers in a central
location, subject to regular quality control, retraining, and
recertification. The diastolic arterial
diameter (DAD) and the arterial diameter change (ADC)
between systole and diastole from the left carotid artery
during cardiac cycles were used for this analysis. Concurrent
brachial BP was measured every 5 minutes with an automated
oscillometric device (1846SX Dinamap), and the mean of 2 BP
measures before the completion of ultrasound examination was used in
calculating arterial stiffness indices. From these diameter
and BP data, the following parameters, needed for
estimating arterial elasticity indices, were assembled for
the entire ARIC cohort: mean DAD, systolic
arterial diameter (SAD), and ADC; carotid
arterial intima-medial thickness (IMT); and
diastolic and systolic blood pressure and pulse
pressure (DBP, SBP, and PP, respectively) (PP=SBP-DBP).
The primary objective of this study was to investigate the prospective
relationship between arterial elasticity and the
development of hypertension. AADC was used as the primary measure of
arterial stiffness, which treated ADC (strain) as the
predictor of incident hypertension and other BP-related variables
(DBP, PP, PP squared, height, and DAD) as covariates to be adjusted for
by the following generalized linear model8 9 :
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BP and Hypertension
At every examination, sitting BP was measured 3 times on each
participant with a random-zero sphygmomanometer, after a 5-minute rest,
by trained technicians following a standardized
protocol.13 The systolic and fifth phase DBP
measurements used in this report are the mean of the second and the
third readings. Study participants were asked to bring all medications,
vitamins, and supplements taken in the 2 weeks before the examination.
The information on pharmacological treatment of hypertension is based
on the participant's self-reported use of any medication to treat high
BP and the transcription and coding of all medication
names.13 Prevalent hypertension at the examination of
arterial stiffness was defined as DBP 90 mm Hg, SBP
140 mm Hg, or use of antihypertensive medication. Incident
hypertension after the arterial stiffness assessment was
defined as DBP 95 mm Hg, SBP 160 mm Hg, or use of
antihypertensive medication during the period.
Other Covariates
Information on age, ethnicity, gender, education levels, and
cigarette smoking status was obtained by standardized questionnaires
administered by trained and certified interviewers. Body mass index
(BMI) was calculated as weight (kilograms)/height
(meters)2. Fasting serum total
cholesterol, triglycerides, and HDL
cholesterol were measured according to standardized
procedures.13 LDL cholesterol was calculated
in participants with triglycerides <400 mg/dL as total
cholesterol minus HDL cholesterol plus one
fifth of triglycerides. Diabetes mellitus was defined as
fasting (8 hours) serum glucose 140 mg/dL, glucose 200 mg/dL if
fasting <8 hours, history of physician-diagnosed diabetes, or use of
an oral hypoglycemic agent or insulin.
Statistical Analysis
Means and SDs for major covariates were obtained from the full
sample and stratified by incident hypertension. An ANCOVA was used to
estimate adjusted means of arterial elasticity as measured
by AADC, Ep, YEM, and ß index and to test the mean differences
comparing persons who developed hypertension with persons who did not
during the follow-up. Logistic regression models were used to estimate
the cumulative incident rate and relative odds of developing
hypertension in relation to baseline arterial elasticity
over 3.3 years of follow-up. SAS (SAS Institute) software was used for
the statistical analyses.
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Results |
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Of 7698 baseline normotensive participants, 91% (6992 individuals) were available for follow-up for
3 years, with an
average follow-up time of 3.3 years. The characteristics of the study
population at the time of arterial stiffness measurement
are presented in Table 1. The
mean age was 56 years, 16% were black, and 56% were women. Compared
with normotensives, persons who developed hypertension during the
follow-up were slightly less likely to have completed high school or
higher education and more likely to have diabetes, a history of
coronary heart disease, and higher levels of baseline
total cholesterol, BMI, and carotid arterial
IMT. They also exhibited higher baseline SBP and DBP levels, although
these values were below the cutoff for hypertension (by definition).
The means (SE) of AADC were 405 (3), 408 (3), 407 (3), and 403 (3)
µm (P=0.57) from the lowest to the highest quartiles of
mean arterial pressure, estimated as (PP/3)+DBP. In
contrast, from the lowest to the highest quartiles of mean
arterial pressure, the means (SE) of Ep were 105 (1), 115
(1), 128 (1), and 157 (1) kPa, respectively (P<0.001).
These results suggest that AADC, as a measure of elasticity, is
independent of BP and that conventional stress-strain ratio indices,
represented here by Ep, are not.
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There were 551 individuals who developed hypertension during the
follow-up, defined as BP 160/95 mm Hg or use of
antihypertensive medication, with a cumulative incidence of 8%. The
mean levels of arterial elasticity, as measured by AADC,
Ep, YEM, and ß index, are presented in Table 2. The mean level of baseline AADC was
lower (indicating a stiffer artery) in persons who developed
hypertension. Similarly, the mean levels of Ep, YEM, and ß index were
higher (also indicating a stiffer artery) in this group. The 3.3-year
cumulative incidence of hypertension, adjusted for age, ethnicity,
gender, center, education, smoking, heart rate, and BMI, by quartiles
of baseline arterial elasticity as measured by AADC, Ep,
YEM, and ß index, are presented in the
Figure. Lower baseline
arterial elasticity levels were associated with higher
cumulative incidence rates of hypertension, and the association was
graded (P for linear trend <0.01 for all 4 measures of
arterial stiffness).
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The incidence odds ratio and 95% CI of developing hypertension
associated with 1 SD decrease of arterial elasticity
measures estimated from multivariate logistic
regression models are presented in Table 3. Lower baseline arterial
elasticity was significantly associated with the development of
hypertension, and the odds of developing hypertension were elevated by
17% for 1 SD (130 µm) decrease in AADC, 52% elevated per 1 SD
increase in Ep (51 kPa), 35% elevated per 1 SD increase in YEM (311
kPa), and 29% elevated per 1 SD increase in ß (3.86 U). After
adjustment of the latter 3 indices as for AADC, all measures of
arterial elasticity, except for YEM, were associated with
incident hypertension of a similar magnitude: 1 SD decrease in
arterial elasticity, estimated from either AADC, Ep, or ß
index, was associated with 
15% increased odds of developing
hypertension (Table 4). Also
presented in Table 4 are the odds ratios of incident
hypertension associated with other hemodynamic factors
when these factors were included in multivariable logistic
regression models with each of the arterial stiffness
indices. All of these hemodynamic factors, except for
heart rate, were associated with the development of hypertension
independent of each other and of population demographic
characteristics.
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We also analyzed the data using lower criteria to define
incident hypertension as BP 140/90 mm Hg (or use of
antihypertensive agents). By this definition, 1033 individuals were
identified as having developed incident hypertension over 3.3 years of
follow-up (a cumulative incidence of 15%). The relationship of
arterial elasticity and incident hypertension was similar
to that found by using the higher cut point definition (data not
shown). The interactions between arterial stiffness and
age, ethnicity, and smoking status in association with the development
of hypertension were tested with the –2 log likelihood ratio test, and
none was found to be statistically significant at
P<0.15.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Most published studies have either used pulse wave velocity as an indirect measure of arterial stiffness or ultrasound-measured elastic modulus (stress-strain ratio and its variants) to assess arterial stiffness.2 7 These stress-strain ratio methods assume a fixed relationship between the change of BP during the cardiac cycle and the change of arterial diameter. Ep, YEM, and ß index are typical examples of traditional stress-strain ratios.4 14 15 Because both the ADC and BP-related variables are included in the formulation of these conventional indices of arterial elasticity, the resulting modulus estimates are not independent of BP. The associations between these stress-strain ratios and any other end point can be attributed to the combination of BP-related measures and/or ADC. The results of PP significantly associated with Ep and no association with AADC provide supporting evidence for these arguments. It has been demonstrated that the aforementioned assumptions for stress-strain modulus are not congruent with the association between the change of BP and the ADC during the cardiac cycle.8 In population samples, the relationship between stress and strain has a non-zero intercept and only modest heteroscedasticity.8 16 To overcome these drawbacks, we have used a non–pressure-related biased estimation of ADC in response to BP change, using component mathematical models to assess ADC, simultaneously controlling for BP and arterial diameter.8 9 This approach, as well as its estimate identified as BP AADC, models the ADC (strain) as an independent variable and treats BP-related variables as covariates in the model. It allows for non-zero intercepts between stress and strain and accounts more fully for the relationship between ADC and BP. It also has the ability to model the nonlinearities of stress-strain relationship, the size of the arteries, and the height of the participants.8 9 In this study, the AADC approach, as well as conventional Ep, YEM, and ß index for comparison with AADC, were used.
Generalized narrowing in smaller arteries (arteriosclerosis) has long been recognized as the major pathophysiological change in essential hypertension.17 18 In contrast, the contribution of decreased elasticity in large to medium-sized arteries in the development of hypertension has not been well documented. Historically, it has been suggested that the increase in SBP with aging, accompanied by increased arterial stiffness in the large arteries, was protective in terms of maintaining sufficient flood flow to the cerebral circulation. Thus, increased SBP and loss of elasticity in large arteries in the elderly had been considered a normative aging process of the arterial wall1 until the treatment of isolated systolic hypertension was identified as both effective and safe in reducing cardiovascular and renal disease events.19 20 Our finding of a graded, temporal relationship between baseline arterial elasticity and the development of hypertension during follow-up examinations provides supporting evidence that the development of hypertension is associated with lower arterial elasticity in the carotid artery. This association cannot be fully explained by age, ethnicity, gender, and other risk factors for hypertension. Although baseline level of BP is a significant predictor of incident hypertension, adjustment for baseline BP level did not diminish the arterial elasticity and hypertension association, except for YEM, which was no longer statistically associated with incident hypertension after adjustment for baseline BP. This departure of YEM from other indices may be due to competing for the variance between IMT (in the YEM formulation) and other BP-related variables in the full model. In these data, the association between elasticity and hypertension is consistent across age, ethnicity, and gender groups (data not shown). Thus, the results from this longitudinal study suggest that impaired elasticity of larger arteries is an antecedent factor in the natural history of BP elevation at the population level.
The development of hypertension in relation to arterial elasticity was seemingly stronger in this population when conventional stress-strain ratios as indices of elasticity were used in comparison to the new mathematical model approach (Table 3). However, this was largely due to the BP-related bias intrinsic to several of the conventional stress-strain measures. After statistical adjustment for BP-related covariates, the associations were of similar magnitude for all 4 indices, as presented in Table 4. To our knowledge, this is the first study to empirically compare the new mathematical modeling approach with the conventional stress-strain ratio approaches in a population sample.
The mechanisms linking large arterial stiffness to the development of hypertension are not clear at present. Although our results were not confounded statistically by other hemodynamic factors, our data suggest that the hemodynamic factors presented in Table 4 are associated with the development of hypertension in this population. It can be hypothesized that greater arterial stiffness (loss of elasticity) in large and medium-sized arteries represents a cumulative adverse impact of conventional risk factors on the arterial wall, and that arterial stiffness, together with its adverse impact on other target organs such as the kidneys, contributes to the development of hypertension. It should be noted that the association between arterial elasticity and the development of hypertension reported here is estimated from observational, population-based empirical testing. The interrelationship between elasticity, structural properties of the large arteries, and the development of hypertension can only be thoroughly investigated by the use of other research methods and techniques.
It is also worth noting that the BP used to estimate arterial stiffness was assessed at the brachial artery, which often overestimates central PP (a key variable in the noninvasive estimation of arterial stiffness in this study).21 22 This study is based on a short follow-up (3.3 years). In addition, we excluded 710 (9% of all baseline normotensives) from this analysis because of loss to follow-up, although their baseline cardiovascular characteristics were similar to those included in this report. Consequently, the generalizability of our findings to the long-term natural history of BP elevation is probably limited. Stiffening of the larger arteries is most likely to be reflected in a fall in DBP, a feature that should be considered in the interpretation of our findings related to incident hypertension. Thus, we anticipate that a stiffening of larger arteries is associated predominately with a sustained elevation of SBP and a corresponding increase in the development of "systolic hypertension." Despite the large sample sizes in this study, our ability to empirically test this expectation is greatly limited by the high proportion of diagnosed and treated hypertension (>75% of incident hypertensives were treated medically in this population). Although the high levels of hypertension detection and treatment are certainly desirable, this result of the efforts by clinical practitioners and public health–oriented campaigns limits the study of the natural history of BP elevation in populations.
As another caveat, we compared the strength of associations between different measures of arterial stiffness and the development of hypertension by using a 1 SD change benchmark (standardized odds ratios, as presented in Tables 3 and 4). This strategy may not be valid in comparing different populations, especially when the independent variables under study are not distributed similarly between populations. Nevertheless, this study represents the first population-based, prospective study to identify lower elasticity (high stiffness) in the common carotid artery as an antecedent factor of hypertension. Additional long-term, population-based follow-up studies are needed to confirm our findings, and studies of a different design are required before it can be concluded that reduced elasticity in large and medium-sized arteries plays a causal role in the development of hypertension.
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 and American Heart Association Scientific Development Award 9730175N. The authors thank the ARIC Study participants and acknowledge the valuable contributions made by the ARIC staff: University of North Carolina at Chapel Hill: Marilyn Knowles and Phyllis Johnson; University of Mississippi Medical Center: Virginia Overman; University of Minnesota: Todd Avant; Johns Hopkins University: Joan Nelling; and Wake Forest University School of Medicine: Delilah Cooke.
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Footnotes |
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Reprint requests to Dr Duanping Liao, Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, H173, 500 University Dr, Hershey, PA 17033.
Received October 5, 1998; first decision November 11, 1998; accepted March 31, 1999.
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 I. Ferreira, R. M. A. Henry, J. W. R. Twisk, W. van Mechelen, H. C. G. Kemper, and C. D. A. Stehouwer The Metabolic Syndrome, Cardiopulmonary Fitness, and Subcutaneous Trunk Fat as Independent Determinants of Arterial Stiffness: The Amsterdam Growth and Health Longitudinal Study Arch Intern Med, April 25, 2005; 165(8): 875 - 882. [Abstract] [Full Text] [PDF]
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S. S. Franklin Arterial Stiffness and Hypertension: A Two-Way Street? Hypertension, March 1, 2005; 45(3): 349 - 351. [Full Text] [PDF]
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J. Dernellis and M. Panaretou Aortic Stiffness Is an Independent Predictor of Progression to Hypertension in Nonhypertensive Subjects Hypertension, March 1, 2005; 45(3): 426 - 431. [Abstract] [Full Text] [PDF]
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C. A. Boreham, I. Ferreira, J. W. Twisk, A. M. Gallagher, M. J. Savage, and L. J. Murray Cardiorespiratory Fitness, Physical Activity, and Arterial Stiffness: The Northern Ireland Young Hearts Project Hypertension, November 1, 2004; 44(5): 721 - 726. [Abstract] [Full Text] [PDF]
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S. Stork, A. W. van den Beld, C. von Schacky, C. E. Angermann, S. W.J. Lamberts, D. E. Grobbee, and M. L. Bots Carotid Artery Plaque Burden, Stiffness, and Mortality Risk in Elderly Men: A Prospective, Population-Based Cohort Study Circulation, July 20, 2004; 110(3): 344 - 348. [Abstract] [Full Text] [PDF]
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A. Y. Bagrov and E. G. Lakatta The Dietary Sodium-Blood Pressure Plot "Stiffens" Hypertension, July 1, 2004; 44(1): 22 - 24. [Full Text] [PDF]
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 K. P. Davy and J. E. Hall Obesity and hypertension: two epidemics or one? Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2004; 286(5): R803 - R813. [Abstract] [Full Text] [PDF]
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A. Scuteri, S. S. Najjar, D. C. Muller, R. Andres, H. Hougaku, E. J. Metter, and E. G. Lakatta Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1388 - 1395. [Abstract] [Full Text] [PDF]
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D. Liao, T. Y. Wong, R. Klein, D. Jones, L. Hubbard, and A. R. Sharrett Relationship Between Carotid Artery Stiffness and Retinal Arteriolar Narrowing in Healthy Middle-Aged Persons Stroke, April 1, 2004; 35(4): 837 - 842. [Abstract] [Full Text] [PDF]
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S. Li, W. Chen, S. R. Srinivasan, and G. S. Berenson Childhood Blood Pressure as a Predictor of Arterial Stiffness in Young Adults: The Bogalusa Heart Study Hypertension, March 1, 2004; 43(3): 541 - 546. [Abstract] [Full Text] [PDF]
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 S. J te Velde, I. Ferreira, J. W. Twisk, C. D. Stehouwer, W. van Mechelen, and H. C. Kemper Birthweight and arterial stiffness and blood pressure in adulthood--Results from the Amsterdam Growth and Health Longitudinal Study Int. J. Epidemiol., February 1, 2004; 33(1): 154 - 161. [Abstract] [Full Text] [PDF]
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I. B Wilkinson and J. R Cockcroft Commentary: Birthweight arterial stiffness and blood pressure: in search of a unifying hypothesis Int. J. Epidemiol., February 1, 2004; 33(1): 161 - 162. [Full Text] [PDF]
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M. de Divitiis, C. Pilla, M. Kattenhorn, A. Donald, M. Zadinello, S. Wallace, A. Redington, and J. Deanfield Ambulatory blood pressure, left ventricular mass, and conduit artery function late after successful repair of coarctation of the aorta J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2259 - 2265. [Abstract] [Full Text] [PDF]
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 E. Suzuki, K. Egawa, Y. Nishio, H. Maegawa, M. Tsuchiya, M. Haneda, H. Yasuda, S. Morikawa, T. Inubushi, and A. Kashiwagi Prevalence and Major Risk Factors of Reduced Flow Volume in Lower Extremities With Normal Ankle-Brachial Index in Japanese Patients With Type 2 Diabetes Diabetes Care, June 1, 2003; 26(6): 1764 - 1769. [Abstract] [Full Text] [PDF]
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M. H. Freitag, M. G. Larson, D. Levy, E. J. Benjamin, T. J. Wang, E. P. Leip, P. W.F. Wilson, and R. S. Vasan Plasma Brain Natriuretic Peptide Levels and Blood Pressure Tracking in the Framingham Heart Study Hypertension, April 1, 2003; 41(4): 978 - 983. [Abstract] [Full Text] [PDF]
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C. Qiu, B. Winblad, M. Viitanen, and L. Fratiglioni Pulse Pressure and Risk of Alzheimer Disease in Persons Aged 75 Years and Older: A Community-Based, Longitudinal Study Stroke, March 1, 2003; 34(3): 594 - 599. [Abstract] [Full Tex |