(Hypertension. 1995;25:71-76.)
© 1995 American Heart Association, Inc.
Articles |
Relation Between Cold Pressor Test and Development of Hypertension Based on 28-Year Follow-up
From the Department of Statistics, Radiation Effects Research Foundation, Hiroshima (F.K.), and the Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki, Japan.
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Abstract |
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Abstract The present study examined the relation between blood pressure reactivity to cold stimulus and the subsequent development of hypertension based on a follow-up study from 1960 through 1988 of 824 normotensive participants (mean age, 35.8±10.8 years) in the Adult Health Study in Nagasaki, Japan. Hypertension developed in 343 individuals during the 28 years of follow-up, with a mean incidence rate of 24.6 per 103 person-years. Confounding variables, including attained age, resting systolic and diastolic blood pressures, and body mass index at baseline, were adjusted using a Poisson regression model. Systolic response was found to be an independent and significant predictor. The relative risk of hypertension for systolic hyperreactors was 1.37, with a 95% confidence interval of 1.10 to 1.71. Diastolic response was significant only when resting diastolic blood pressure was also considered. The cold pressor test appears to be useful if performed on middle-aged subjects older than 40 years at the time of examination, when hypertension is more prevalent. The current results support the hypothesis that hyperre- activity is a predictor of the development of hypertension.
Key Words: cold • follow-up studies • hypertension, essential • prognosis
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Introduction |
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Many studies have shown hypertension to be a major risk factor for cerebrocardiovascular morbidity and mortality.1 2 3 4 5 6 Therefore, early identification of the risk of hypertension would be important to its prevention. The cold pressor test, in which the response of blood pressure to the stimulus of external cold is measured, has been used in attempts to identify apparently normotensive individuals who might develop hypertension.7 8 9 10 11 12 However, reports are contradictory regarding whether this test is useful for predicting hypertension.13 14 15 16 17 18
In 1960, the cold pressor test was performed on 1198 participants in the Adult Health Study in Nagasaki, Japan. These participants were subsequently followed for 28 years. Few long-term prospective studies of the cold pressor test on so many subjects have been done. Therefore, the present study examines the effectiveness of the cold pressor test as a predictor of hypertension.
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Methods |
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Subjects
The Adult Health Study sample was established in 1958 to observe the late effects of radiation exposure among atomic bomb survivors in Hiroshima and Nagasaki.19 20 Of the total sample, 1198 males and females, 15 to 81 years of age, took part in a cold pressor test program at the Radiation Effects Research Foundation (its predecessor, the Atomic Bomb Casualty Commission) Nagasaki facility from May to November 1960 as part of a study of accelerated aging caused by radiation exposure. The program was done according to procedures approved by the Research Protocol Committee at the Radiation Effects Research Foundation. A report on the composition of these participants and the blood pressure response to cold has been previously published, indicating no difference in response caused by radiation exposure.21
Since the present study was aimed at investigating the relation between blood pressure response to cold and the development of hypertension, 289 people were excluded from the study who had hypertensive diseases or a resting systolic blood pressure (SBP) higher than 140 mm Hg and/or resting diastolic blood pressure (DBP) higher than 90 mm Hg at baseline. In addition, follow-up after the cold pressor test was not available for 60 individuals, and cold pressor test results were unknown for 11. Body mass index (BMI) (weight [kilograms]/height [meters squared]), which is associated with the development of hypertension, was unknown for 14. A total of 824 individuals were included in the present study (Table 1).
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Ascertainment of Hypertension
These 824 individuals had been followed through the biennial
Adult Health Study medical examinations, which include blood pressure
measurements at rest and medical history questionnaires. Resting blood
pressure was measured on the right arm with a standard mercury
sphygmomanometer after at least 5 minutes of rest with subjects in the
sitting position. The first and fifth Korotkoff phases were recorded as
SBP and DBP, respectively. A medical history was taken to identify
medically treated cases of hypertension occurring in the interval of
the biennial examinations. Hypertension, defined as SBP greater than or
equal to 160 mm Hg and/or DBP greater than or equal to 95 mm Hg or as
the use of antihypertensive medication, has been recorded and
accumulated in the Adult Health Study clinical diagnoses database using
the International Classification of Disease code. The cutoff date of
the follow-up was 30 June 1988. The onset of hypertension was defined
as the date midway between the examination when hypertension was first
diagnosed and the previous examination.
Cold Pressor Test
After subjects had rested supine for at least 20 minutes
in a room maintained at 25° to 30°C, resting blood pressure was
measured in the right upper arm with a standard mercury
sphygmomanometer. The left hand was then immersed to just above the
wrist in cold water (3° to 5°C) for 1 minute; blood pressure
measurements were obtained at 30, 60, and 120 seconds after immersion.
The maximal changes in SBP and DBP from resting values during cold
stimulus were defined as systolic response and diastolic response,
respectively. Each response was positive in most subjects except the
systolic response in eight cases and the diastolic response in six
cases. Fig 1 shows the frequency distributions of
systolic and diastolic responses. Both distributions indicate that the
frequency of systolic and diastolic responses drops sharply between 10
to 14 and 15 to 19 mm Hg. Therefore, those subjects whose systolic
(diastolic) response exceeded 15 mm Hg were defined as systolic
(diastolic) hyperreactors. Table 1 shows resting blood pressure,
response, and frequency of hyperreactors by sex and age.
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Statistical Methods
The relation of cold pressure response to incidence of
hypertension was examined by Poisson regression analysis. When the
data were stratified by sex, age at baseline, follow-up period,
radiation dose, BMI, resting SBP, resting DBP, systolic response, and
diastolic response, the number of subjects who developed hypertension,
y, in each stratum is assumed to be an independent Poisson
variable with the expected value of E(y)=PYx
, where PY
and are the person-years at risk and the hypertension risk, or
hazard, in each stratum. Stratification was done as shown in Table 2, giving a total of 1934 strata.
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The risk function, , considered here was based on an excess relative
risk (RR) model, which can be written as
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where exp(X) is the background risk defined
exponentially by a linear function of covariates, X, such as
sex, mean values of attained age, resting SBP, resting DBP, BMI, and
radiation dose computed for each stratum. The attained age is
calculated as age at baseline plus year since baseline in each stratum.
The term Response is a variable representing systolic or diastolic
response to cold. When the risk of hypertension between hyperreactors
and normal reactors was compared, the term Response was treated as a
binary indicator variable, with 0=systolic (diastolic) hyperreactor and
1=systolic (diastolic) normal reactor. Therefore, after controlling for
covariates X, the RR of hypertension for hyperreactors is
1+
xexp(z), relative to normal reactors. The term
z is a factor modifying the response, in an exponential
fashion, that included sex, mean values of age at baseline, and
radiation dose. We also examined the relation of blood pressure
response to incidence of hypertension, treating the term Response as
mean value of blood pressure response in each stratum without treating
it as a binary variable. Parameters in the risk function were estimated
based on the maximum likelihood method, and the significance of
parameters was based on the likelihood ratio test.22
Since exposure to radiation is peculiar to our sample, radiation dose is considered as one of the covariates in the present study. The radiation dose assigned individually to atomic bomb survivors is based on the Dosimetry System (DS86) introduced in March 1986 after reassessment of atomic bomb doses.23
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Results |
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For the 824 normotensive individuals (326 males, 498 females), mean age at baseline was 35.8 years and mean resting blood pressure was 115.7/68.3 mm Hg. Mean systolic response was 12.6±10.1 mm Hg (±SD), and mean diastolic response was 12.4±8.9 mm Hg. No difference was observed between the two responses (Table 1).
Hypertension developed in 343 of 824 normotensive individuals during the study period of 1960 to 1988. The crude incidence rate of hypertension was 24.6 per 103 person-years (28.3 for males and 22.3 for females).
Characteristics of Hyperreactors and Normal Reactors
Table 3 shows a comparison of the background
characteristics and incidence rates of hypertension between
hyperreactors and normal reactors. Significantly higher mean age at
baseline in the systolic hyperreactor group was observed compared with
the systolic normal reactor group. Resting DBP in the diastolic
hyperreactor group was significantly lower than that of the diastolic
normal reactor group.
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Both the crude and age-adjusted incidences of hypertension were higher in the systolic hyperreactor group than in the systolic normal reactor group. The diastolic hyperreactor group had a higher rate of hypertension than the diastolic normal reactor group after adjustment for resting DBP, which was significantly different between the two groups.
Fig 2 shows a comparison of the incidence of hypertension between normal reactors and hyperreactors by resting SBP and DBP, respectively. The incidence is higher for the hyperreactors in all categories of resting blood pressure. Fig 3 plots incidence rates of hypertension per 103 person-years for systolic normal reactors and hyperreactors during the subsequent 5, 10, 15, 20, and 28 years of follow-up since baseline by age at baseline. The incidence rates of hypertension for systolic hyperreactors were clearly higher than those for normal reactors in the groups older at baseline even during the first 5 years since baseline. This tendency was not remarkable among the groups younger at baseline, but the rates were generally higher for hyperreactors of all ages.
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) and hyperreactors (
) by
age at baseline and years since baseline, Nagasaki, Japan, 1960 to
1988. Hypertension incidence rate was calculated by summing the cases
that developed hypertension and person-years for the subsequent 5, 10,
15, 20, and 28 years of follow-up since baseline.
Risk of Hypertension Development Among Hyperreactors Based
on Poisson Regression Analysis
Background risk of hypertension was considered based on attained
age, not on age at baseline, because the development of hypertension is
more strongly associated with attained age. The obtained background
risk was significantly dependent on attained age, the square of
attained age, resting SBP, resting DBP, and BMI. Sex difference was not
significant after resting blood pressure was considered
[
2(1)=0.85]. The dependence on radiation dose
category was not significant [2(4)=2.70].
After controlling for attained age, the square of attained age, resting SBP, resting DBP, and BMI as the background risk, the RR of hypertension for systolic hyperreactors compared with systolic normal reactors was 1.37, with a 95% confidence interval (CI) of 1.10 to 1.71. Exclusion of resting SBP from the background risk did not materially alter this 37% increase in risk.
When the variable Response in the RR model represents mean value
of systolic response in each stratum, its coefficient was estimated at
0.022 with a 95% CI of 0.006 to 0.045. The quadratic term of Response
was not significant [2(1)=0.03]. This means a
44% linear increase of the risk for an increase of 20 mm Hg in
systolic response. None of the factors modifying systolic response,
including sex, age at baseline, and radiation dose, were
significant.
After controlling for significant covariates as the background risk,
the RR of hypertension for diastolic hyperreactors compared with
diastolic normal reactors was 1.34, with a 95% CI of 1.06 to 1.68.
When resting DBP was excluded from the background risk, diastolic
response turned out to be nonsignificant
[2(1)=1.36]. This is different from the case
of systolic response.
We also examined the relation between diastolic response and hypertension risk by treating the term Response as mean value of diastolic response in each stratum. Coefficient of Response was estimated to be 0.037 with a 95% CI of 0.013 to 0.076. The quadratic term of Response was not significant, and there was no significant modifier for the diastolic response.
Significance of Cold Pressor Test in Relation to Age at
Baseline
We examined the difference in the effectiveness of the cold
pressor test as a predictor of hypertension by dividing the study
subjects into two age groups, using 40 years at baseline as the
dividing line. Table 4 shows the RR values of systolic
hyperreactors compared with those of systolic normal reactors by age at
baseline, adjusted for attained age, the square of attained age, BMI,
resting SBP, and DBP. The RR was 1.19 (not significant) for the <40
year old group and 1.62 (significant) for the 
40 year old group. This
indicates, as suggested in Fig 3, that if the cold pressor test were
performed on middle-aged subjects, it would be more effective as a
predictor of hypertension in later years.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Of the 1198 participants in the cold pressor test program, 824 normotensive subjects at baseline were included in the present study to examine the relation between blood pressure response to cold and the development of hypertension based on the 28-year follow-up study. Crude cumulative incidence of hypertension over the 28-year follow-up period increased with age, from 31% to 39%, 57%, and 57% among normotensive subjects aged 29 years or younger, 30 to 39, 40 to 49, and 50 years or older at baseline. It is interesting to compare these rates with those of a national survey of circulatory disorders conducted in 1990,24 which is a cross-sectional survey based on a random sample of about 10 000 Japanese men and women aged 30 years or older. The survey indicates that prevalence rates of hypertension (
160 and/or 95 mm Hg or receiving antihypertensive
treatment) are 5%, 16%, 30%, 43%, and 56% for subjects aged 30 to
39, 40 to 49, 50 to 59, 60 to 69, and 70 years or more, respectively,
which are almost similar to the crude cumulative incidence rates at the
ages our study subjects attained by the end of the 28-year follow-up
period. Among the covariates considered as background risks, resting SBP, DBP, and BMI at baseline were found to be significant predictors for hypertension. BMI is a well-known important risk factor for hypertension.2 25 26 It is also well known that baseline SBP and DBP strongly influence the development of hypertension.26 27 28 Sex was a significant factor in a univariate model, with the incidence rate of males being higher than that of females. However, the significance of sex disappeared after adjustment was made for higher resting blood pressure in males than in females. Whether radiation exposure contributes to the progression of hypertension is a problem peculiar to our sample. However, radiation exposure was not significant in the present study as either a background risk or a possible modifier of the relation between blood pressure response and development of hypertension.
A systolic hyperreactor to cold has been generally defined as having a systolic response of more than 20 mm Hg and a diastolic hyperreactor as having a diastolic response of more than 15 mm Hg; however, these cutoff points are not necessarily consistent among investigators, because there is no cutoff point that naturally divides a hyperreactor from a normal reactor. In the present study, systolic and diastolic hyperreactors were both defined as more than 15 mm Hg because no difference was observed between the two response distributions.
The stress test is based on the hypothesis that a latent period of blood pressure hyperreactivity precedes progression to sustained hypertension and that the increased response is evoked under stress. Our results support the hypothesis that hyperreactivity is more or less a predictor of hypertension, in agreement with several previous studies by Wood et al,14 Barnett et al,15 and Hines.29 However, other studies on medical students16 17 and flight students18 have not confirmed the usefulness of the cold pressor test as a predictor of hypertension. Recently, Menkes et al30 reported on a study that demonstrated the effectiveness of the cold pressor test based on the results of a 20- to 36-year follow-up of 910 medical students. This study is comparable to ours in the number of study subjects, follow-up period, and the use of the survival analysis. Menkes et al applied Cox regression analysis in the adjustment for confounding factors such as age at baseline, resting blood pressures, BMI, smoking history, and updated family history of hypertension and reported that systolic response was a significant and independent predictor of hypertension. This result is similar to ours. However, they observed no significance in diastolic response. Our present study showed that diastolic response was not a predictor by itself but became significant only when considered along with resting DBP. Diastolic response might act as a predictor in supplementing resting DBP. Our study had some advantage in terms of a wide age range, from 15 to 81 years at baseline, so it was possible to examine the effectiveness of the cold pressor test by age at baseline. Our findings indicate that the cold pressor test would be an effective predictor if performed on middle-aged subjects older than 40 years, when they become more prone to develop hypertension. In the present study the difference in hypertension incidence rates between normal reactors and hyperreactors among the younger age group at baseline did not reach statistical significance. However, whether younger hyperreactors develop hypertension more frequently than normal reactors if they are followed into later decades remains unsolved. As our study subjects have been followed beyond 1988, this issue will be evaluated.
It may be meaningful to associate the significance of blood pressure response in the cold pressor test with other interesting results. In a follow-up study of blood pressure in a fixed population, the initial level is likely to be high. The environment in which the initial measurement is taken is a so-called psychic pressor test,29 involving nervous stress, and the transient increase of blood pressure reflects an "alarm reaction" to the nervous stress.31 Many follow-up studies have shown that progression to hypertension is different in those individuals who show a transient increase under the above-mentioned nervous stress compared with those who do not show such an increase, even though they have normal resting blood pressure.2 29 32 33 Many reports also describe the significant relation between the development of hypertension and blood pressure response caused by psychological stress7 8 and isometric and dynamic exercise.9 10 11 12
Few follow-up results are available concerning the cold pressor test. Many studies should be done to allow a definite conclusion regarding the usefulness of the cold pressor test in predicting hypertension. The results obtained from a single measurement of blood pressure response to some external stimulus must be carefully interpreted.34 Nevertheless, the agreement of two large, long-term prospective studies by Menkes et al and us in demonstrating the significance of hyperreactivity independently using the survival analysis not used in previous studies seems to indicate the usefulness of the cold pressor test as a predictor of hypertension.
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Acknowledgments |
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This publication is based on research protocol RP 19-61 and manuscript MS 08-94 concerning research performed at the Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan. RERF is a private nonprofit foundation funded equally by the Japanese Ministry of Health and Welfare and the US Department of Energy through the National Academy of Sciences.
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Footnotes |
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Reprint requests to Fumiyoshi Kasagi, Department of Statistics, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima 732, Japan.
Received April 13, 1994; first decision May 26, 1994; accepted September 14, 1994.
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K. A. Matthews, K. Salomon, S. S. Brady, and M. T. Allen Cardiovascular Reactivity to Stress Predicts Future Blood Pressure in Adolescence Psychosom Med, May 1, 2003; 65(3): 410 - 415. [Abstract] [Full Text] [PDF]
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F. A. Treiber, T. Kamarck, N. Schneiderman, D. Sheffield, G. Kapuku, and T. Taylor Cardiovascular Reactivity and Development of Preclinical and Clinical Disease States Psychosom Med, January 1, 2003; 65(1): 46 - 62. [Abstract] [Full Text] [PDF]
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D. Carroll, G. D. Smith, M. J. Shipley, A. Steptoe, E. J. Brunner, and M. G. Marmot Blood Pressure Reactions to Acute Psychological Stress and Future Blood Pressure Status: A 10-Year Follow-Up of Men in the Whitehall II Study Psychosom Med, September 1, 2001; 63(5): 737 - 743. [Abstract] [Full Text] [PDF]
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R. M. Kelsey, S. M. Patterson, M. Barnard, and B. S. Alpert Consistency of Hemodynamic Responses to Cold Stress in Adolescents Hypertension, December 1, 2000; 36(6): 1013 - 1017. [Abstract] [Full Text] [PDF]
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R. M. Kelsey, B. S. Alpert, S. M. Patterson, and M. Barnard Racial Differences in Hemodynamic Responses to Environmental Thermal Stress Among Adolescents Circulation, May 16, 2000; 101(19): 2284 - 2289. [Abstract] [Full Text] [PDF]
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K. C. Light, S. S. Girdler, A. Sherwood, E. E. Bragdon, K. A. Brownley, S. G. West, and A. L. Hinderliter High Stress Responsivity Predicts Later Blood Pressure Only in Combination With Positive Family History and High Life Stress Hypertension, June 1, 1999; 33(6): 1458 - 1464. [Abstract] [Full Text] [PDF]
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S. A. Everson, G. A. Kaplan, D. E. Goldberg, and J. T. Salonen Anticipatory Blood Pressure Response to Exercise Predicts Future High Blood Pressure in Middle-aged Men Hypertension, May 1, 1996; 27(5): 1059 - 1064. [Abstract] [Full Text]
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