Aortic Stiffness Is an Independent Predictor of Progression to Hypertension in Nonhypertensive Subjects
Aortic stiffness may predict progression to hypertension beyond classic risk factors. In a longitudinal study, we assessed the predictive value of aortic stiffness on future hypertension in nonhypertensive subjects with blood pressure (BP) <140/90. Aortic stiffness was determined by echocardiography at baseline in 2512 subjects. The follow-up time was 4 years. A stepwise increase in hypertension incidence occurred across the male and older participants: 3.8% of young female individuals, 11.5% of young male, 26.1% of old female, and 58.8% of old male subjects progressed to hypertension over 4 years. In multivariate analysis, aortic stain, distensibility, and stiffness index (β) remained significantly associated with the progression to future hypertension after adjustment to classic risk factors in men and women and in young and old populations. This study provides the first direct evidence to our knowledge in a longitudinal study that aortic stiffness is an independent predictor of progression to hypertension in nonhypertensive individuals.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (The JNC 7 Report) defines that hypertension patients have a systolic blood pressure (BP) ≥140 mm Hg or a diastolic BP ≥90 mm Hg.1 It is well known that hypertension is an independent risk factor for cardiovascular events; the risk of cardiovascular disease, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg.1,2 BP values tend to trend over time; individuals who are normotensive at 55 years of age have a 90% lifetime risk for hypertension.1 However, the prediction of future BP and the identification of future hypertension from baseline values have proved difficult.3
Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with essential hypertension.4–6 Furthermore, aortic stiffness constant is the best single predictor of acute coronary syndromes.6,7 Aortic stiffness may predict sustained hypertension; in patients with hypertension and hypothyroidism and in patients with repaired coarctation of aorta, sustained hypertension is caused by the increased aortic stiffness.8,9 The aim of the present study was to increase the reliability of prediction of future BP by using aortic stiffness in nonhypertensive subjects who were followed-up in our outpatient department.
A total of 2571 subjects (1460 women and 1111 men), aged 35 to 94 years, entered the study. This population included subjects examined in our outpatient department, and they were free of the following exclusion criteria: hypertension (systolic BP ≥140 mm Hg or a diastolic BP ≥90 mm Hg, or the use of antihypertensive medication); overt cardiovascular disease or symptoms; and history of a myocardial infarction or of congestive heart failure. None of these patients was referred for typical symptoms of coronary heart disease or other cardiovascular disease. All participants gave informed consent.
Four years later, all participants were re-examined and aortic stiffness was measured again. The coexistence of metabolic or endocrine conditions affecting aortic stiffness was studied by the routine clinical examination and determination of hormones by specific laboratory tests. Some participants (239; 9.5%) started on BP-altering medication during the follow-up period. Before measurements, any medication was discontinued for at least 5 half-lives before the study. A total of 2512 subjects (1440 women and 1072 men), aged 35 to 94 years, were successfully re-examined after 4-year interval. Fifty-nine (2.3%) subjects were lost from observation. Twenty-one deaths have occurred, 11 of them caused by cardiovascular events and the rest caused by cancer.
BP Measurement in the Office
BP measurements were obtained on 3 occasions with 15 days of time difference between each measurement. The average value of these measurements was obtained as the reference BP. The auscultatory method of BP measurement with a properly calibrated and validated instrument was used. Subjects were seated quietly for at least 5 minutes in a chair, with feet on the floor and arm supported at heart level. A cuff bladder encircling at least 80% of the arm was used. Two measurements were made. Systolic BP is the point at which the first of 2 or more sounds are heard (phase 1) and diastolic BP is the point before the disappearance of sounds (phase 5).1 The average of these 2 readings was used to classify participants into nonhypertensive JNC 7 BP category of normal (systolic <140 mm Hg and diastolic <90 mm Hg).1
Laboratory Tests, Lifestyle Characteristics, and Anthropometric Measurements
Fasting plasma routine tests and lipids were assessed. Venous blood was collected in the morning, after the subjects had abstained from all food and drink for at least 12 to 16 hours and from vigorous activity for at least 12 hours.
Lifestyle characteristics were ascertained by completion of a questionnaire and checked by interview. Level of physical activity and leisure time physical activity were determined for all subjects. All subjects completed logs describing the type of exercise undertaken; its frequency and duration and were characterized as either sedentary or active. “Active” included any type of isotonic exercise (jogging, cycling, swimming, etc) at least 3 times per week for >45 minutes each time.
We collected information on alcohol consumption, cigarette smoking, demographic variables, and personal and family histories relevant to hypertension. All subjects were divided into 2 groups with respect to the amount of alcohol consumed; group 0 indicates <1 can of beer or <1 glass of wine or <1 drink of spirit per week, and group 1 indicates ≥1 can of beer or ≥1 glass of wine, or ≥1 drink of spirit per week.
Standing height was measured to the nearest 0.5 cm. Body weight was measured to the nearest one-tenth of a kilogram. Body mass index was calculated using the formula weight (kg)/height (m)2.
Aortic Stiffness Measurement
The transverse displacement of the aortic wall was measured with commercially available equipment (Image Point; Hewlett Packard) with a 2.5-MHz transducer. After routine conventional echocardiographic examination, patients were placed in a left mild recumbent position and the ascending aorta was recorded in the 2-dimensional–guided M-mode tracings. The protocol was similar to that used in previous studies.9–11 The aortic diameter was recorded by M-Mode echocardiogram at a level of 3 cm above the aortic valve. Internal aortic diameters were measured by means of a caliper in systole and diastole as the distance between the trailing edge of the anterior aortic wall and the leading edge of the posterior aortic wall.
Aortic systolic (AoS) diameter was measured at the time of full opening of the aortic valve and diastolic (AoD) diameter was measured at the peak of QRS complex of the electrocardiogram. Ten consecutive beats were measured routinely and averaged. Measurements were performed by the same investigator; the intra-observer variability of aortic diameter measurements was 2.3%. The percentage change of the aortic root was calculated as %ΔAo = 100 × (AoS − AoD)/AoD to obtain the aortic strain.9,11,12 Aortic distensibility was calculated from the formula: ΔΑ : (Α× PP)=π× [(AoS/2)2 − (AoD/2)2]: [π× (AoD/2)2× PP], with A being the cross-sectional lumen area and PP being pulse pressure.13 A was estimated as the product of π by r2; where r was the AoS/2 or AoD/2. The aortic stiffness index (β) was calculated:9,11–15 β=ln (SBP/DBP)/(AoS−AoD)/AoD (pure number), where SBP is systolic BP and DBP is diastolic BP. Like BP measurements, aortic stiffness index was calculated on 3 occasions and the average value of these measurements was used as the reference aortic stiffness index.
Patients were divided in 4 groups according to their age (median value, 65 years) and sex: young female, young male, old female, and old male. Changes in variables were defined as follow-up minus baseline value. Analysis of variance (ANOVA) was used to calculate the difference between the groups concerning continuous variables and χ2 for categorical variables. Repeated measures ANOVA was used to calculate the difference in measurements between baseline and 4 years later; group variable was used as the between subjects factor. We used multivariable linear regression models16,17 to examine whether aortic strain, distensibility, and stiffness index at baseline predict an increase in BP after adjusting for baseline BP and other baseline risk factors. This was performed separately for systolic BP, diastolic BP, and pulse pressure. Then, we performed a model that looked at change in risk factors (body mass index, aortic strain, distensibility, and stiffness index) in relation to change in BP.
First, we establish a base model that includes known predictors of BP increase over time; these predictors were age-squared, body mass index, heart rate, total cholesterol, physical activity, alcohol, smoking, and diabetes mellitus. All variables were included in the model. Then, we tested whether aortic strain, distensibility, and stiffness index (β) add to this model. Aortic stiffness, BP, and age have markedly nonlinear relations; thus, an age-squared term was used. Similarly, men and women may differ in terms of the role that aortic stiffness plays in hypertension. Thus, data were analyzed separately by sex.
A forward conditional logistic regression model for progression to hypertension with the baseline systolic BP, diastolic BP, age-squared, body mass index, heart rate, total cholesterol, physical activity, alcohol, smoking, and diabetes mellitus (separately by sex) as potential covariates tested the prediction of incident hypertension by each of the aortic stiffness variables (strain, distensibility, and stiffness index).
Analysis was performed using SPSS REGRESSION with Collinearity Diagnostics option and assistance from SPSS EXPLORE for evaluation of regression assumptions. All statistical assumptions were met and no multicollinearity problems were found to exist in our analysis. All associations were considered to be significant at P<0.05.
Table 1 shows the clinical characteristics of participants in the 4 categories: young females, young males, old females, and old males. Men and old individuals had increased systolic BP, diastolic BP, and pulse pressure compared with women and to young individuals (P<0.001). Similarly, heart rate, body mass index, total cholesterol, and diabetes mellitus were increased in men compared with women and in old compared with young participants (P<0.001). Aortic strain and distensibility were increased in young individuals compared with old and in women compared with men (P<0.001), whereas aortic stiffness was increased in old subjects and in men compared with young subjects and women (P<0.001). Progression to hypertension was more frequent in old participants and in men than in young persons and in women (P<0.001).
Table 2 shows the BP, heart rate, body mass index, and aortic elastic properties indexes at baseline compared with the end of the 4-year period. Except for heart rate all other parameters showed significant changes after the 4-year period (P<0.001). The interaction between time and age, as well as time and sex, was significant for all variables except for heart rate (P<0.001).
We used 3 indexes of aortic elastic properties: aortic strain, aortic distensibility, and aortic stiffness index (β). Table 3 shows the linear regression models in women and Table 4 shows the lineal regression models in men. The results were similar when analyzed separately above and below the median age. Each Table is divided into 3 parts for the 3 dependent variables: change in systolic BP, diastolic BP, and pulse pressure, respectively. For each part, the first 3 lines show the results of the base model with the 3 independent predictors, BP, age-squared, and body mass index, which show significant association with the dependent variable. All other variables were forced into the model. The next 6 lines show the aortic strain, distensibility, and stiffness index and their changes, which are the only variables that entered the models and are significantly associated with the dependent variables.
All indexes predicted an increase in BP after adjusting for baseline BP and the other risk factors; R2 was increased for change in systolic BP, in diastolic BP, and in pulse pressure when strain was added in the base model (Tables 3 and 4⇑). Similar increases were found for aortic distensibility and stiffness in all groups (Tables 3 and 4⇑). First, we perform one model based on baseline data only and we found that baseline BP, age, and body mass index were the predictors of change in BP. This model was performed separately for systolic BP, diastolic BP, and pulse pressure; the predictors of change were the same (Tables 3 and 4⇑). Furthermore, a separate model looked at change in risk factors (change in body mass index, heart rate, strain, distensibility, and stiffness index). Changes in aortic strain, distensibility, and stiffness index were independent predictors of changes in systolic BP, diastolic BP, and pulse pressure. R2 was increased for change in systolic BP, in diastolic BP, and in pulse pressure when strain was added in the base model (Tables 3 and 4⇑). Similar increases were found for aortic distensibility and stiffness in all groups (Tables 3 and 4⇑).
Using multiple linear regression analysis, we found that activity level at baseline was not related to aortic stiffness or to stiffness progression. In contrast, stiffness progression was predicted by age (B=0.011), sex (B=0.16), and systolic BP (B=0.179) (R2=0.11, P<0.001), and B was the unstandardized coefficient of the regression model. The forward stepwise model included stiffness progression (aortic stiffness index change) as the dependent variable and age, sex, systolic BP, diastolic BP, pulse pressure, systolic and diastolic aortic diameter, body mass index, heart rate, total cholesterol, physical activity, diabetes mellitus, alcohol, and smoking as independent predictors.
Tables 5 and 6⇓ show the results of the logistic regression analysis in men and women, respectively; all aortic stiffness variables predicted the progression to hypertension along with systolic BP, diastolic BP, and age. Each stiffness variable has entered the model separately with all other covariates: systolic BP, diastolic BP, age-squared, body mass index, heart rate, total cholesterol, physical activity, alcohol, smoking, and diabetes mellitus
Progression to hypertension in normotensive subjects depends on age and sex; thus, in young females, young males, old females, and old males, the percent increase in BP after 4 years of follow-up was 3.8%, 11.5%, 26.1%, and 58.8%, respectively; aortic stiffness also predicts transition to hypertension. Aortic stiffness, BP, and body mass index were increased over time and were predictors of the increase in BP. Aortic strain, distensibility, and stiffness index and their changes predicted the increase in systolic BP, diastolic BP, and pulse pressure after adjusting for baseline BP and other baseline risk factors like heart rate, total cholesterol level, physical activity, alcohol consumption, smoking, and diabetes mellitus.
Our findings are in accordance with a previous study by Liao et al,18 the Atherosclerosis Risk In Communities (ARIC) study, which has shown that lower arterial elasticity (high stiffness) in the common carotid artery is related to the development of hypertension. The authors hypothesized that greater arterial stiffness in large and medium 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 kidneys, contributes to the development of hypertension.
Aortic stiffness indexes were evaluated by means of aortic strain adjusted by BP, distensibility, and stiffness index. All parameters predicted progression of BP over a 4-year interval. Methodological considerations should be taken into account before the results become accepted. Pulse pressure was measured at the site of brachial artery, which does not truly reflect aortic pulse pressure because of the pulse pressure amplification phenomenon. In patients older than 50 years, this amplification phenomenon is attenuated.
Aortic stiffness was a predictor for both women and men and in younger and older participants. However, men and older individuals have greater increase in BP and in aortic stiffness over time, as shown in Table 2. The incremental effect of aortic stiffness indexes on prediction of BP progression was shown by the increase in R2 value in multivariate models when aortic indexes were entered into the regression models. Aortic indexes increase the predictive value of the models even after adjusting for baseline BP values. The present study has added to the previous ones19,20 the baseline aortic elastic properties indexes and the increase of these indexes as important determinant of future increase in BP. These variables increased the reliability of prediction of future BP in multivariable analyses by 6% to 9%, as shown by the R2 increment when aortic indexes were added to the base models.
Previous studies demonstrated that arterial stiffness was an independent predictor of cardiovascular mortality in end-stage renal disease21,22 and in essential hypertensive patients.4,5 However, the predictive value of aortic stiffness on future BP increase has not previously been established for individuals with normal BP. Although one could argue that change in BP was the reason for change in stiffness index, several mechanisms may explain the association between increased aortic stiffness and progression to hypertension. Aortic stiffness is a cause of premature return of reflected waves in late systole increasing central aortic pressure.23,24 Thus, increased aortic stiffness is associated with increased afterload. Consequently, the elevation of afterload raises systolic BP.24
Second, cardiovascular risk factors for hypertension such as baseline age cause increased aortic stiffness.4,6,15,18,23 The measurement of aortic stiffness integrates the cumulative effects of these factors on the elastic properties of the aortic wall. Because most of the determinants of aortic stiffness index are also risk factors for hypertension, it is mandatory to verify that the predictive value of aortic stiffness index on future hypertension remained significant after adjustment for these risk factors.
It is concluded that in a population of nonhypertensive subjects with no overt cardiovascular disease or symptoms at baseline, aortic elastic properties measured through trans-thoracic echocardiogram predicted the increase in systolic BP, diastolic BP, and pulse pressure beyond the prediction provided by risk factors including initial level of BP, assessed through a multivariate model. This study provides the first direct evidence in a longitudinal study that aortic elastic properties at baseline and increased stiffening of the aorta on follow-up were important determinants of future increases in BP. These findings link aortic stiffness to the future risk of hypertension. Our results show that measuring aortic stiffness helps to identify patients at high risk for hypertension and serve to re-emphasize the importance of preserve aortic function in the primary prevention of hypertension. These results held true for both young and old people, as well as for men and women.
- Received October 4, 2004.
- Revision received October 19, 2004.
- Accepted January 21, 2005.
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