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22
High-Normal Blood Pressure Progression to
Hypertension in the Framingham Heart Study
Mark Leitschuh, L. Adrienne Cupples, William Kannel,
David Gagnon, and Aram Chobanian
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This study sought to determine if individuals with high-normal blood pressure (diastolic blood
pressure of 85-89 mm Hg) progress to hypertension more frequently than those with normal
blood pressure (diastolic blood pressure less than 85 mm Hg), thus advancing to a higher
cardiovascular risk category. Individuals from the Framingham Heart Study were placed in
normal and high-normal blood pressure categories and followed for 26 years for the
development of hypertension. With hypertension defined as a diastolic blood pressure of 95
mm Hg or greater or the initiation of antihypertensive therapy, 23.6% of men and 36.2% of
women with normal blood pressure developed hypertension compared with 54.2% of men and
60.6% of women with high-normal blood pressure. The relative risk for the development of
hypertension associated with high-normal blood pressure was 2.25 for men (95% confidence
interval [CI], 1.8-2.8; /?<0.0001) and 1.89 for women (95% CI, 1.5-2.3; /><0.0001). The
age-adjusted relative risks estimated by the proportional hazards model were 336 for men and
337 for women (/><0.001). Among those risk factors examined, baseline systolic and diastolic
blood pressure, Metropolitan relative weight, and change in weight over time were significant
predictors of future hypertension in men and women whose initial blood pressure was normal.
For men with high-normal blood pressure, systolic blood pressure and change in weight were
identified as risk factors for future hypertension. These results indicate that the probability of
individuals with blood pressure in the high-normal range developing hypertension is twofold to
threefold higher than in those with normal blood pressure. Therefore, we recommend that
persons with high-normal blood pressure be followed up with frequent blood pressure testing
and counseled on modification of risk factors. (Hypertension 1991;17:22-27)
I
n 1984, the Joint National Committee on the
Detection, Evaluation, and Treatment of High
Blood Pressure introduced the concept of highnormal blood pressure, responding to concerns that
even modest elevations in blood pressure previously
considered normal may promote increased risk of
premature cardiovascular morbidity and mortality.1
High-normal blood pressure was defined as a diastolic blood pressure of 85-89 mm Hg compared with
the normal diastolic blood pressure of less than 85
mm Hg. Although definite cardiovascular risk is associated with this level of blood pressure,2 undetermined is whether the reduction in the blood pressure
From the Cardiovascular Institute, the Evans Department of
Clinical Research, and the Section of Preventive Medicine and
Epidemiology, Boston University School of Medicine, Boston,
Mass.
Supported by grants HL-18318 (Hypertension SCOR), HL07224, and contract NO1-HV-92922 from the National Heart,
Lung, and Blood Institute, National Institutes of Health.
Address for correspondence: Mark Leitschuh, MD, Department
of Cardiology, Medical College of Wisconsin, 8700 West Wisconsin Avenue, Milwaukee, WI 53226.
Received March 6,1990; accepted in revised form August 20,1990.
to the normal level would reduce this risk. One
important factor would influence the decision of
whether to reduce such modest blood pressure elevations to more optimal levels with nonpharmacological means: the possibility that individuals with highnormal blood pressure progress to hypertension at a
greater rate than those with strictly normal blood
pressure, thus advancing to a higher cardiovascular
risk category that may indicate a need for treatment.
If this process were to occur, then attempts to
prevent this progression by modification of known
risk factors for the development of hypertension
would seem indicated. Therefore, we have used the
30-year follow-up data from the Framingham Heart
Study to determine the rate of progression from
high-normal blood pressure to hypertension compared with that of normal blood pressure; we also
examined some possible risk factors associated with
the development of hypertension in both groups.
Methods
The cohort of 5,209 men and women from the
Framingham Heart Study were first examined be-
Leitschuh et al Progression to Hypertension
tween 1949 and 1952 and have been followed up for
32 years with biennial exams. Each examination
included extensive cardiovascular history and physical exam, an electrocardiogram, and two physicianmeasured blood pressure determinations. Systolic
and fifth-phase diastolic blood pressure readings
were taken from the left arm with a mercury sphygmomanometer with the subject seated. Data on the
use of antihypertensive agents was gathered by interview of the subjects, starting with the fourth exam
(1958-1960). Before that exam, few oral antihypertensive agents were available and hypertension was
grossly undertreated.
Initial Categorization of Normal and High-Normal
Blood Pressure
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Individuals from the cohort were initially placed in
normal and high-normal blood pressure categories,
which were based on the average physician-measured
blood pressures from the first three biennial exams.
Normal blood pressure was defined as an average
diastolic blood pressure of less than 85 mm Hg and a
systolic blood pressure of less than 140 mm Hg. Highnormal blood pressure was defined as an average
diastolic blood pressure of 85-89 mm Hg and a systolic blood pressure of less than 140 mm Hg. Individuals excluded from categorization were those with the
following conditions: 1) preexisting coronary heart
disease, defined by clinical or electrocardiographic
evidence of angina pectoris or myocardial infarction;
2) other preexisting cardiovascular disease, defined by
evidence of claudication or cerebrovascular disease; 3)
current or prior left ventricular hypertrophy on electrocardiogram; 4) cardiomegaly on chest radiograph;
and 5) other conditions requiring antihypertensive
medications. Individuals with preexisting coronary artery disease were excluded because of the possible
effect of antiangjnal therapy or myocardial infarction
on blood pressure. Those persons with cerebrovascular or other peripheral vascular disease were excluded
because of the possible effect of such disease on
accurate blood pressure measurement. Those individuals with cardiomegaly or left ventricular hypertrophy
were excluded to eliminate persons with congestive
heart failure or "burnt-out" severe hypertension who
showed normal or high-normal blood pressure.
23
pressure had occurred in those who developed hypertension, we repeated the analysis, with 95 mm Hg
as the cutoff level for defining hypertension. All
further analyses, including those of risk factors, use
the latter definition of hypertension.
Risk Factors for the Development of Hypertension
The following potential risk factors for the development of hypertension (diastolic blood pressure 95
mm Hg or greater) were averaged over exams 1-3
and evaluated: 1) Metropolitan relative weight (percentage), 2) glucose intolerance (diagnosis of diabetes mellitus, glucose in urine, or fasting blood glucose
of greater than 120 mg/100 ml), 3) initial systolic
blood pressure (mm Hg), 4) initial diastolic blood
pressure (mm Hg), 5) vital capacity-height index
(ml/in.), 6) fasting cholesterol (mg/100 ml), 7) hemoglobin (percentage), 8) cigarettes smoked (number/
day), and 9) alcohol consumption (oz/mo). Alcohol
consumption was determined by a single questionnaire during the interview of participants at their
biennial exam, asking for the usual intake per week.
Other risk factors, including family history of hypertension and dietary factors such as salt intake, which
have been reported to be important in the development of hypertension, were not included in the initial
data base of the Framingham Heart Study and consequently were not included in this analysis. Additionally, weight change from the average at exams 1,
2, and 3 to the weight at the exam in which hypertension was diagnosed was compared with the weight
change for those in whom hypertension did not
develop followed up for a similar time period (exam
9). The weight was expressed as the Quetelet index,
which is defined as pounds per inch of height squared
multiplied by 100. Comparison of the risk factors
among those in whom hypertension developed and
those in whom it did not was evaluated with the t
(continuous measures) and x2 (categorical measures)
tests and linear regression analysis to adjust for age
at exam 3. Proportional hazards models were used to
evaluate the multivariate relation between these
measures and the development of hypertension.
Results
Development of Hypertension
Initial Categorization of Blood Pressure and
Progression to Hypertension
The development of hypertension was determined
in those individuals placed in high-normal and normal blood pressure categories at exam 3 and followed
up for 26 years to exam 16. Those who died are
included in the analysis up to the time of death. The
analysis to determine the percentage of individuals
who developed hypertension was conducted on two
separate occasions by the use of two different blood
pressures to define hypertension. First, hypertension
was defined as a physician-measured diastolic blood
pressure of 90 mm Hg or greater on two consecutive
biennial exams or the initiation of antihypertensive
therapy. To insure that significant increases in blood
Table 1 shows the progression of normal and
high-normal blood pressure to hypertension when
hypertension was defined as a diastolic blood pressure of 90 mm Hg or greater or the initiation of
antihypertensive therapy. Among those with normal
blood pressure, hypertension developed in 33% of
men and 42% of women compared with 71% of men
and 78% of women with high-normal blood pressure.
The relative risk for the development of hypertension
associated with high-normal blood pressure was 2.1
for men (95% confidence interval, 1.8-2.5) and 1.9
for women (95% confidence interval, 1.6-2.3;
p<0.0001 for both). Similar results were obtained
24
Hypertension
Vol 17, No 1, January 1991
TABLE 1. Progression to Hypertension (Diastolic Blood Pressure 90 mm Hg or Greater) Over 26-Year Follow-up
Period Based on Initial Blood Pressure, Sex, and 10-Year Age Groups
Women
Men
Age
n
Hypertensive n{%)
205
305
78 (38.5%)
105 (34.4%)
47 (27.3%)
12 (27.9%)
249 (33.2%)
Hypertensive n(%)
n
Normal blood pressure
30-39
40-49
50-59
60-69
Total
172
68
750
365
492
198
42
1,097
170 (46.6%)
203 (41.2%)
72 (36.3%)
14 (33.3%)
459 (41.9%)
High-normal blood pressure
30-39
40-49
50-59
60-69
Total
31 (77.5%)
54(76.1%)
22 (56.4%)
1 (33.3%)
108 (70.6%)*
40
71
39
3
153
16 (76.2%)
44 (84.6%)
14 (66.7%)
3 (60.0%)
77 (77.7%)t
21
52
21
5
99
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Normal blood pressure, diastolic blood pressure less than 85 mm Hg and systolic blood pressure less than 140 mm Hg;
high-normal blood pressure, diastolic blood pressure of 85-89 mm Hg and systolic blood pressure less than 140 mm Hg.
•Mantel-Haenzel relative risk, 2.11; 95% confidence interval, 1.81-2.50; /XO.0001.
tMantel-Haenzel relative risk, 1.90; 95% confidence interval, 1.60-2.30;/><0.0001.
when we used the definition of hypertension as a
diastolic blood pressure of 95 mm Hg or higher or the
initiation of antihypertensive therapy (Table 2). Although the number and percentage of hypertensive
individuals was smaller, the relative risk associated
with high-normal blood pressure was nearly the
same. These results suggest that it is twice as probable that hypertension will develop in both men and
women with high-normal blood pressure than in
those with normal blood pressure.
Figures 1 and 2 plot the age-adjusted incidence of
hypertension, which was estimated by the proportional
hazards model for men and women. Both men and
women with high-normal blood pressure have a higher
incidence of hypertension compared with those with
normal blood pressure. The age-adjusted risk for the
development of hypertension was 336 for men and 337
for women by this form of analysis (p< 0.001).
Risk Factors for the Development of Hypertension
Tables 3 and 4 show the age-adjusted means for
those variables studied as potential risk factors for
the development of hypertension in men and women
with normal and high-normal blood pressure. For
individuals with normal blood pressure, baseline systolic and diastolic blood pressure and Metropolitan
relative weight for both men and women were statistically significant risk factors. For women only, serum
cholesterol was also a significant predictor of future
hypertension. For men only with high-normal blood
pressure, diastolic blood pressure was a significant
risk factor.
TABLE 2. Progression to Hypertension (Diastolic Blood Pressure 95 mm Hg or Greater) Over 26-Year Follow-up
Period Based on Initial Blood Pressure, Sex, and 10-Year Age Groups
Women
Men
Age
n
Hypertensive n(%)
205
305
172
51 (24.9%)
78 (25.6%)
36 (20.9%)
12(17.6%)
177 (23.6%)
n
Hypertensive n{%)
Normal blood pressure
30-39
40-49
50-59
60-69
Total
68
750
High-normal blood pressure
30-39
40
40-49
71
50-59
60-69
Total
39
3
153
19 (47.5%)
47 (66.2%)
16 (41.0%)
1 (33.3%)
83 (54.2%)*
365
492
198
42
1,097
21
52
21
5
99
139 (38.0%)
184 (37.4%)
64 (32.3%)
10 (23.8%)
397 (36.2%)
7 (33.3%)
39 (75.0%)
12(57.1%)
2 (40.0%)
60 (60.6%)t
Normal blood pressure, diastolic blood pressure less than 85 mm Hg and systolic blood pressure less than 140 mm Hg;
high-normal blood pressure, diastolic blood pressure of 85-89 mm Hg and systolic blood pressure less than 140 mm Hg.
•Mantel-Haenzel relative risk, 2.25; 95% confidence interval, 1.81-2.79;/><0.001.
tMantel-Haenzel relative risk, 1.89; 95% confidence interval, 1.55-2.31; p<0.001.
rtenaion
Leitschuh et al
s
V
Percent 1
t
a
Progression to Hypertension
25
100
80
70
80
50
FIGURE 1. Line grap/i showing age-adjusted risk of
hypertension developing in men over time according to
initial diastolic blood pressure group. Relative risk for
high-normal group is 3.36.
^>
3020100.
r
/"*
2
4
6
. -——"~
8
10
12
- Normal Diaatolic BP
14 16
Years
IB 20
22
24
26
26
30
High Normal Diaatolic BP
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Multivariate Cox regression analyses confirmed
that initial systolic and diastolic blood pressure were
predictors of hypertension in men and women whose
initial blood pressure was normal (p<0.001). Systolic
blood pressure in men and diastolic blood pressure in
women with high-normal blood pressure were also
significant. If one eliminates from the analysis the
powerful effect of blood pressure, the Metropolitan
relative weight is seen to be an independent predictor of hypertension (p<0.05). As shown in Table 5, a
10% increase in Metropolitan relative weight confers
an approximate 20-25% increased risk for the development of hypertension.
Figure 3 presents the results of an analysis done
to determine if a change in weight over time might
be a significant risk factor for the development of
hypertension. Men with normal and high-normal
blood pressure and women with normal blood pressure in whom hypertension developed had a statistically significant gain in weight compared with
those in whom it did not develop. Hypertension
developed in women with high-normal blood pressure who also gained weight, but this correlation
failed to reach statistical significance, possibly because of the relatively small number of individuals
in the group. Those in whom hypertension did not
develop, despite high-normal blood pressure, demonstrated a significant loss of weight.
Discussion
The primary objective of this study was to determine if individuals with high-normal blood pressure
progress to hypertension at a greater rate than those
with strictly normal blood pressure. We have shown
that it is at least twofold more probable for hypertension to develop in individuals with high-normal
blood pressure than in those with normal blood
pressure. These results confirm previous studies that
have found the level of initial blood pressure to be
predictive of the development of hypertension but
more clearly define the risk for the specific group of
individuals with high-normal blood pressure.3"9
The analysis of potential risk factors for the development of hypertension discloses the importance of
systolic and diastolic blood pressure as predisposing
factors for both men and women with normal blood
pressure. For men with high-normal blood pressure,
only diastolic blood pressure was significant. Mean
relative weight for men and women and serum cholesterol level for women with normal blood pressure
were also statistically significant contributors. If one
compares the normal with the high-normal group,
TABLE 3. Initial Age-Adjusted Mean Values for Possible Risk Factors for the Development of Hypertension
Normal blood pressure
Women
Men
Risk factors
Metropolitan relative weight (%)
Glucose intolerance (%)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Vital capacity-height index (ml/in.)
Cigarettes smoked (noVday)
Serum cholesterol (mg/100 ml)
Hemoglobin (%)
Alcohol consumption (oz/mo)
Values expressed as mean±SEM.
•p<0.05; tp<0.001;
Normotensive
Hypertensive
113.3±0.6
7.8 ±1.0
119.1±0.3
75.7±0.2
382.2±2.5
14.8±0.5
219.5±1.5
14.1±0.1
19.3±1.3
115.4±1.1*
8.7±2.0
124.6±0.6f
78.6±0.4f
377.8±4.5
14.3±0.9
219.6±2.7
14.0±0.1
21.3±2.4
Normotensive
110.3 ±0.6
4.1±0.7
116.6±0.3
73.7+0.2
277.9±1.7
6.8±0.3
216.9±1.4
12.6±0.1
7.6±0.6
Hypertensive
114.1 ±0.7t
2.9±0.9
121.8±0.4t
76.7 ±O3t
275.8 ±2.2
7.3±0.4
221.7±1.8*
12.6±0.1
7.8±0.8
26
Hypertension Vol 17, No 1, January 1991
0 100
0
SO
1 80
V
70
a.
80
1
FIGURE 2. Line graph showing age-adjusted risk of
hypertension developing in women over time according
to initial diastolic blood pressure. Relative risk for
high-normal group is 3.37.
SO
o 40
•c
30
Q
"Og
20
£c
10
a.
0
2
4
8
8
10 12 U 18 18 20 22 24 28 28 30
Years
- Normal Diastolic BP
High Normal Diastolic BP
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persons with high-normal blood pressure are seen to
have higher Metropolitan relative weights than those
with normal blood pressure. As shown in Figure 3,
the weight change over time also appears to be
important for the prediction of hypertension. Individuals who became hypertensive gained more weight
than those who remained normotensive. This factor
failed to reach statistical significance for women with
high-normal blood pressure, perhaps because the
number in this group was small. Concomitantly, these
data would suggest that weight loss in those above
optimum desirable weight and avoidance of weight
gain are important in the prevention of hypertension.
Previous studies have suggested that alcohol consumption may contribute to the development of hypertension,10 but individuals must consume a relatively
large amount of alcohol every day for this to occur. In
the total Framingham cohort, no increase was seen in
the incidence of hypertension until more than 29
ounces of alcohol each month was consumed.11 In this
subset of the cohort, alcohol consumption was modest
(men, 19-24 oz/mo; women, 7-8 oz/mo), which may be
why we failed to identify it as a predictor of hypertension. Finally, because alcohol consumption was determined by questionnaire and had no independent validation, these results are less reliable than those risk
factors that were actually measured.
A number of limitations of this study should be
considered while interpreting the results. Not all risk
factors now considered important in the development of hypertension were initially included in the
Framingham Heart Study; therefore, they were not
included in this analysis. This omission also holds for
nutritional factors such as salt intake. Results from
the INTERSALT study showed that sodium excretion was significantly and independently related to
systolic blood pressure. In terms of this relation,
Stamler12 has estimated that a reduction in the
population sodium intake of 100 mmol/day would
result in an average population systolic blood pressure that was at least 2.2 mm Hg lower. In addition,
the Framingham population consisted of primarily
white, middle-class individuals with an underrepresentation of different minority and socioeconomic
groups. Also, the number of individuals in the older
age groups was small, especially in the high-normal
blood pressure group. Because of these limitations,
the results and recommendations of the study should
be considered with caution when applied to elderly
and minority subjects.
An important question arises from the findings of
this study. Is the progression from high-normal blood
pressure to hypertension preventable without exposure of this large population to the risks and cost of
TABLE 4. Initial Age-Adjusted Mean Values for Possible Risk Factors for the Development of Hypertension
High-normal blood pressure
Men
Risk factors
Women
Normotensive
Hypertensive
Normotensive
Hypertensive
Metropolitan relative weight (%)
Glucose intolerance (%)
122.1 + 1.6
121.9±1.5
12.8+3.5
6.1±3.2
122.6±3.8
6.4±3.9
121.5±2.6
4.4±2.7
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Vital capacity-height index (ml/in.)
129.3±0.6
87.1 ±0.2
131.5±1.0*
87.4±0.1
131.1±1.0
131.4±0.7
380.7±7.0
87.3±0.7
264.5±5.0
Cigarettes smoked (noVday)
390.9±3.6
12.3±1.7
87.1±0.3
272.6±7.3
230.8±4.5
14.4±0.1
21.7±4.2
12.2±U
227.4±4.1
14.0±0.1
23.7±3.9
7.4±0J
Serum cholesterol (mg/100 ml)
Hemoglobin (%)
Alcohol consumption (oz/mo)
230.2±6.0
13.0±0.1
7.5±2.9
8.9±0.7
224.1 ±4.2
13.2±0.1
Values expressed as mean±SEM.
•p<0.01.
7.0±2.0
Leitschuh et al
TABLE 5. Stepwise Proportional Hazards Analysis of Risk Factors
for the Development of Hypertension (Dlastolic Blood Pressure 95
mm Hg or Greater) in Subjects With Normal Blood Pressure
Risk factors
Units
Relative risk
p value
10
0.99
1.22
0.0682
Men
Age at exam 3
Metropolitan relative weight
Women
Age at exam 3
Metropolitan relative weight
10
10
10
0.84
1.26
0.8972
0.0411
0.0003
Variables considered in model are: age at exam 3 (forced into
model), glucose intolerance, cholesterol, cigarettes smoked per
day, hemoglobin, vital capacity, and alcohol consumption (oz/mo).
Units are change in 10 years for age and 10% change for
Metropolitan relative weight.
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pharmacological antihypertensive therapy? Two recent clinical trials have reported the ability to prevent
the development of hypertension in individuals with
normal or high-normal blood pressure by dietary or
hygienic means. In the Primary Prevention of Hypertension study,13 individuals who were prone to hypertension (i.e., those who had high-normal blood pressure [a first-screen diastolic blood pressure of 80-89
mm Hg with a second-screen value of 85-89
mm Hg]) or had normal blood pressure (80-89
mm Hg) with obesity or a rapid pulse rate were
randomly assigned to an intervention or control
group. The goals of intervention were a reduction in
weight with a fat-modified, American Heart Association-type diet, reduction in daily sodium intake and
alcohol consumption, and an increase in physical
activity. The incidence of hypertension over the
5-year trial was 8.8% for the intervention group and
19.2% for the control group (odds ratio, 2.4). In the
Hypertension Prevention Trial,14 841 men and
women with diastolic blood pressures of 78-89
|
0.30,
H
0.25-
3
0.20:
©
0.15:
O
•a
s
| Not HyjwrtensiTo
\£j Hypertensive
MEN
WOMEN
0.10:
or
0.05-
~
0.00
ft
-0.10 ^
-0.16
p=.Q01
p=.0034
p=.0Q01
Normal
Hifh
Normal
Normal
Hifh
Normal
FIGURE 3. Bar graph showing change in Quetelet Index
([poundsI square inch)'x 100) by hypertension status at end of
follow-up period, adjusted for age and by initial diastolic blood
pressure group for men and women.
Progression to Hypertension
27
mm Hg were randomly assigned to a control treatment group or one of four dietary counseling groups
(reduced calories, sodium, sodium and calories, or
reduced sodium and increased potassium). In all
treatment groups, blood pressure decreased below
the level of controls. These results indicate the feasibility of preventing the progression to hypertension by
nonpharmacological means, but further study is
needed to determine the benefits of such intervention.
In summary, we have provided specific epidemiological information regarding the risk of hypertension for
individuals with high-normal blood pressure. Recent
trials have suggested the feasibility of preventing the
development of hypertension by nonpharmacological
means, and further trials seem warranted to determine
the benefits of such interventions in the prevention of
cardiovascular morbidity and mortality.
References
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3. Apostolides AY, Cutter G, Daugherty SA, Detels R, Kraus J,
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of blood pressure. Arch Intern Med 199O;150:153-162
KEY WORDS
risk factors
blood pressure
•
essential hypertension
High-normal blood pressure progression to hypertension in the Framingham Heart Study.
M Leitschuh, L A Cupples, W Kannel, D Gagnon and A Chobanian
Hypertension. 1991;17:22-27
doi: 10.1161/01.HYP.17.1.22
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Copyright © 1991 American Heart Association, Inc. All rights reserved.
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