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(Hypertension. 1996;27:324-329.)
© 1996 American Heart Association, Inc.
Articles |
Exercise Blood Pressure Predicts Mortality From Myocardial Infarction
From the Department of Internal Medicine, Central Hospital of Akershus, Nordbyhagen, and the Division of Cardiology, Department of Internal Medicine, Ullevaal University Hospital (S.E.K.), Oslo, Norway.
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Abstract |
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Abstract Apparently healthy men (n=1999, 40 to 59 years old) were investigated from 1972 through 1975 to determine whether systolic blood pressure during bicycle ergometer exercise predicts morbidity and mortality from myocardial infarction beyond that of casual blood pressure taken after 5 minutes of supine rest. During a follow-up of 31 984 patient-years (average, 16 years), 235 subjects had myocardial infarctions, of which 143 were nonfatal and 92 were fatal. Exercise blood pressure was more strongly related than casual blood pressure to both morbidity and mortality from myocardial infarction. Among 520 men with casual systolic blood pressure
140 mm Hg, 304 increased their systolic blood pressure to
200 mm Hg during 6 minutes of exercise at an initial workload of 600
kpm/min. These 304 men had an excessive risk of myocardial infarction
(18.8% versus 9.5% among the 1294 men with casual blood pressure
<140 mm Hg and exercise blood pressure <200 mm Hg;
P<.001). As many as 58% of those with myocardial
infarction in this group died, compared with 33% (range, 26% to 35%)
for all other groups (P=.0011), including those with casual
blood pressure 140 mm Hg and exercise blood pressure <200 mm Hg.
Thus, exercise blood pressure is a stronger predictor than casual blood
pressure of morbidity and mortality from myocardial infarction, and an
early rise in systolic blood pressure during exercise adds
prognostic information about mortality from myocardial infarction among
otherwise healthy middle-aged men with mildly elevated casual blood
pressure. We suggest that blood pressure taken during standardized
exercise testing may distinguish between severe and less severe
hypertension.
Key Words: blood pressure • morbidity • mortality • exercise test • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Hypertension is associated with increased cardiovascular mortality1 and morbidity.2 In most epidemiological studies, casual blood pressure has been measured. Conceivably, other measurements of blood pressure, such as pressure readings during basal conditions,3 ambulation,4 5 6 or exercise,7 may be better risk indicators. Filipovsky et al8 found that the exercise-induced increase of systolic blood pressure was a risk factor for death from cardiovascular as well as noncardiovascular causes independent of resting blood pressure after 17 years of follow-up in 4907 men.
Recently, we9 found that cardiovascular
mortality during a mean follow-up of 16 years in 1999 apparently
healthy men was strongly related to both casual blood pressure as
measured after 5 minutes of supine rest and to exercise
systolic blood pressure measured in the sitting position during
a standardized bicycle test (peak systolic blood pressure at
the initial moderate workload of 6 minutes at 600 kpm/min [
100 W,
5880 J/min]). The influence of blood pressure at 600 kpm/min was so
strong that the independent predictive value of casual blood pressures
became nonsignificant when analyzed simultaneously
as a continuous variable. Among the 520 men with casual
systolic blood pressure 140 mm Hg, 304 increased their
systolic blood pressure to 200 mm Hg during 6 minutes of
exercise at the initial workload of 600 kpm/min. These 304 men had a
16-year cardiovascular death rate of 16.1% compared
with 6.0% among those with a systolic blood pressure <200 mm
Hg at 600 kpm/min (n=216, P=.025). The
cardiovascular death rate was also 6.0% among men who
were normotensive at rest (n=1479). Thus, we found that an early rise
of systolic blood pressure during exercise adds prognostic
information about cardiovascular mortality among
otherwise healthy middle-aged men with mildly elevated casual blood
pressure.9
We also investigated whether exercise blood pressure measured as described above serves as a predictor of morbidity and mortality from myocardial infarction beyond that provided by casual blood pressure and independent of other cardiovascular risk factors as previously reported.10 We can now report such data after having completed 14 to 17 years (average, 16 years) of follow-up on clinical status in >90% of those who survived.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Subjects
During the years 1972 through 1975, male employees aged 40 to 59 years employed by five companies and governmental agencies in Oslo, Norway, were invited to participate in a survey of the prevalence of latent coronary heart disease and other cardiovascular diseases. They were recruited through the healthcare system of their companies and for years were acquainted with routine medical examinations that included measurements of blood pressure. All subjects with known or suspected cardiovascular diseases, including those receiving antihypertensive drug treatment, and men with diabetes mellitus; malignancy; disorders of the locomotor system that prevented them from performing a symptom-limited bicycle exercise test; or advanced pulmonary, liver, renal, and other chronic diseases or disorders were excluded. Further details about the selection procedures and exclusion criteria have been presented elsewhere.10 11 12 Of 2341 eligible men, 2014 (86%) apparently healthy, white men participated.
Protocol
Informed consent was obtained from all subjects.
They were
examined between 7:30 and 10 am after having abstained from eating for
at least 12 hours and from smoking for at least 8 hours. The baseline
examination program included a comprehensive case history, physical
examination, measurement of casual blood pressure and heart rate,
routine blood tests including serum cholesterol and
triglyceride levels, an intravenous glucose
tolerance test, chest radiograph, electrocardiogram
(ECG), and an ECG-monitored symptom-limited bicycle exercise test.
Cholesterol and triglyceride levels were
determined by standardized methods.13 As a measure of
glucose tolerance, the rate of glucose disappearance after
intravenous injection of 50 mL 50% glucose (in percent per
minute=K-value) was used.14
Blood pressure measurements were made after familiarization with the laboratory and were performed with a mercury sphygmomanometer both at rest and during exercise. Resting blood pressure (casual blood pressure) was taken after 5 minutes in the supine position in a quiet room and was measured three times. All measurements in all subjects were done by the same physician. The fifth phase of the Korotkoff sounds was used to establish diastolic blood pressure. There was a systematic fall in blood pressure from the first to the second reading and then on average a small rise in blood pressure (<1 mm Hg) from the second to the third reading. It was therefore decided to use the second reading for prognostic evaluation (the baseline recording).
Resting heart rate was measured for exactly 1 minute with a stopwatch before the blood pressure readings. Maximum heart rate was taken from the exercise ECGs and virtually always was the last value recorded immediately before termination of the exercise test. Heart rates associated with ectopic rhythms in some subjects were not included.
All
subjects performed a symptom-limited exercise test on an
electrically braked Elema bicycle.15 Systolic
blood pressure was measured every other minute. The initial workload of
this test was 600 kpm/min (100 W, 5880 J/min) and lasted for 6
minutes. The peak systolic blood pressure at this workload,
which in almost all subjects was the third recording, was used
for further scrutiny. Increments in workload were thereafter made in
steps of 300 kpm/min (50 W) every 6 minutes. All subjects were
encouraged to continue exercising until exhaustion, while adhering to
common safeguards for terminating the test.10 15 The
maximum systolic blood pressure was also recorded for
further scrutiny but was not related to clinical outcome
measures.9 A final measurement was always performed just
before termination of the test. The total work performed was the sum of
the work done at each of the workloads.10 Maximal workload
tolerated was defined as the highest workload tolerated for 1
minute.
Exercise testing was repeated within 2 weeks in 130 of the participants. Blood pressure, heart rate, and working capacity in the two tests were within ±5% in 90% of the men and within ±10% in all of them, proving excellent reproducibility.
Six hundred kpm/min was
selected as the starting load because it was
judged that apparently healthy, middle-aged men would be able to
start cycling at this load and continue the test for at least 6
minutes. This decision was based on a presurvey pilot study in which
all 80 subjects were able to complete this load for 6 minutes. However,
in the main study, 15 men proved unable to complete 6 minutes
exercising at the initial load. The 1999 men who were included were all
able to continue into the 900 kpm/min load; 600 kpm/min proved on
average to represent approximately 55% of the mean maximal
workload tolerated for 1 minute.
The follow-up time ranged from 14 to 17 years, with an average of 16 years. Information about time and cause of death was ascertained from the Norwegian Central Bureau of Statistics as described elsewhere.10 15 The accuracy of this register is very high because almost 70% of middle-aged men who died in Oslo throughout the years of the study underwent autopsy. The mortality data are given as of December 31, 1989, and are 100% complete. The specific causes of death are given according to the International Classification of Diseases, version 9, and have been classified as either cardiovascular or noncardiovascular by one of the authors.9 10
During the total follow-up of 31 984 patient-years, 278 deaths occurred, of which 150 were due to cardiovascular and 128 to noncardiovascular diseases. Of the cardiovascular deaths, 92 were caused by acute myocardial infarction or sudden unexpected death very likely caused by acute myocardial infarction.9 10
After 7
years, the clinical status of 92% of those still alive was
retested according to the same protocol, and after 14 to 17 years
(average, 16 years) this was repeated in >90% of the survivors. By
scrutinizing records in the local hospitals and records in the
offices of physicians employed by the companies for whom the subjects
worked, 143 cases of nonfatal myocardial infarction were detected,
which increased the number of myocardial infarctions to a total of 235.
Since all clinically diagnosed myocardial infarctions were treated in
hospitals within a limited geographic area, complete information was
easily obtained on almost all myocardial infarctions. A diagnosis of
myocardial infarction was given to men who became acutely ill during
follow-up and who fulfilled at least two of the following
criteria15 : (1) typical chest pain of 30 minute
duration; (2) typical enzyme pattern during the acute phase, with a
peak value of AST, creatine phosphokinase (CPK), or lactic
dehydrogenase (LDH) (including isoenzyme) that exceeded the upper
normal limit of the respective laboratory by a factor of 2; and (3)
development of a Minnesota Code of 1.1 during the acute phase. If
enzymes could not be studied, a myocardial infarction was diagnosed in
the presence of criteria 1 and 3. Most subjects were hospitalized with
all three criteria; however, silent myocardial infarction was accepted
in 8 subjects according to the ECG criteria (Minnesota Code 1.1)
alone.
Statistics
The association between time until myocardial
infarction, fatal
or nonfatal outcome, and blood pressure was studied by means of
proportional-hazards models16 in which casual blood
pressure, age, smoking habit, serum cholesterol and
triglyceride levels, body mass index, K-value (see above),
resting and maximum heart rates, and total workload performed during
the exercise test (exercise capacity10 ) were included as
possible covariates in addition to peak blood pressure at the 600
kpm/min load. The main assumption in these models is that there is a
proportional relation between the change in the value of a variable
and the change in the associated hazard.
By analyzing blood pressures as continuous variables for assessing the risk of dying from cardiovascular disease (the relative risk of dying associated with increments of 2 SDs), additional multivariate analyses were performed to test the predictive value with consideration of both casual (systolic and diastolic) and exercise blood pressures as covariates.
The proportional-hazards assumption for the
model was found to be
fulfilled. The model was computed with the use of the
proportional-hazards general linear model procedure in the SAS
computer package. When comparing frequencies, we applied the
2 test, and when two groups of persons were
compared according to a continuous variable, we used a
two-sided Wilcoxon rank-sum test.17 The
correlation between two continuous variables was assessed by
Spearman's correlation method.17
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Morbidity and mortality from myocardial infarction gradually increased with increasing casual systolic (Table 1
) and
diastolic blood pressures (data not
shown) and with increasing pulse pressure
(systolic-diastolic blood pressure, data not
shown). Peak exercise systolic blood pressure at 600 kpm/min
(Table 2) but not maximum systolic blood
pressure during the exercise test (data not shown) was also related to
morbidity and mortality from myocardial infarction.
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The relative risk of myocardial infarction associated with an increment of 35.7 mm Hg (equal to 2 SD) in casual systolic blood pressure was highly significant when adjusting for all other cardiovascular risk factors measured in the present study but became nonsignificant when also adjusting for peak exercise systolic blood pressure at 600 kpm/min (P=.21). The relative risk of myocardial infarction associated with an increment of 48.5 mm Hg (equal to 2 SD) in peak systolic blood pressure at 600 kpm/min was also significant when adjusting for age, smoking habit, and all the other variables introduced as covariates in the present study, including resting casual blood pressures (P=.023).
Among the 520 men with mildly elevated casual systolic blood
pressure (140 mm Hg), 304 increased their systolic blood
pressure to 200 mm Hg during 6 minutes at the starting exercise
workload of 600 kpm/min (from 158±14 to 218±17 mm Hg,
respectively).
These men had an 18.8% risk of myocardial infarction versus 9.5%
among the 1294 men with casual systolic blood pressure <140 mm
Hg (121±10 mm Hg) and exercise systolic blood pressure <200
mm Hg (169±15 mm Hg) (Fig 1; P<.001).
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According to Cox regression analysis, these results could not
be explained by differences in casual blood pressures, age, or resting
and exercise heart rates or by traditional
cardiovascular risk factors such as body mass index,
smoking habit, serum cholesterol and
triglyceride levels, glucose tolerance, and total work
performed (exercise capacity). Table 3 shows the results
when the men with combined casual systolic blood pressure 140
mm Hg and exercise systolic blood pressure 200 mm Hg (n=304)
were compared with all others (n=1695).
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The group with mildly elevated casual systolic blood pressure
(140 mm Hg, 148±8 mm Hg, n=216) and exercise systolic blood
pressure <200 mm Hg (183±11 mm Hg) had an intermediate risk of
myocardial infarction (15.7%; Fig 1
) that was not significantly
different when directly compared with the men with 18.8% risk (n=304;
P>.10).
Of the 57 men who had myocardial infarctions in the group of 304 men
with combined casual systolic blood pressure 140 mm Hg and
exercise systolic blood pressure 200 mm Hg, 33 (58%) died
during follow-up compared with 33% (range, 26% to 35%) for all
other groups (P=.0011, Fig 2), including
groups of 216 men with casual systolic blood pressure 140 mm
Hg and exercise systolic blood pressure <200 mm Hg and 185 men
with casual systolic blood pressure <140 mm Hg and exercise
systolic blood pressure 200 mm Hg. These results could not be
explained by differences in casual blood pressures, age, or resting and
exercise heart rates or by traditional cardiovascular
risk factors such as those listed above. With the Cox regression model,
mortality from myocardial infarction in the group with casual and
exercise blood pressures 140 mm Hg and 200 mm Hg, respectively, was
significantly higher (P<.01) when directly compared with
the group with casual and exercise blood pressures 140 mm Hg and
<200 mm Hg, respectively.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present study, 1999 apparently healthy men, initially aged 40 to 59 years, were followed up for a mean period of 16 years. During a total follow-up of 31 984 patient-years, there were 235 subjects with myocardial infarction, of which 143 were nonfatal and 92 had an early or late fatal outcome. Exercise blood pressure was more strongly related than casual blood pressure to morbidity and mortality from myocardial infarction. Among the 520 men with casual systolic blood pressure
140 mm Hg, 304 increased their
systolic blood pressure to 200 mm Hg during 6 minutes at the
starting exercise workload of 600 kpm/min. These men had an excessive
risk of myocardial infarction (18.8% versus 9.5% among the 1294 men
with casual blood pressure <140 mm Hg and exercise blood pressure
<200 mm Hg; P<.001). As many as 58% (33 of 57) of those
with myocardial infarction in this group died compared with 33%
(range, 26% to 35%) for all other groups (P=.0011),
including those with casual blood pressure 140 mm Hg and exercise
blood pressure <200 mm Hg (n=216). Thus, an early rise of
systolic blood pressure during exercise seems to add prognostic
information on mortality from myocardial infarction among otherwise
healthy middle-aged men with mildly elevated casual blood pressure.
These results add to what we have previously reported9
about the influence of exercise systolic blood pressure on
cardiovascular mortality. Our results could not be explained by differences in casual blood pressures, heart rate at rest or during exercise, age, sex, or race, or by traditional risk factors such as smoking habit, body mass index, serum cholesterol or triglyceride levels, glucose tolerance, or exercise capacity.10 The prognostic importance of exercise blood pressure was thus present when we used the Cox regression model to correct for the possible influence of these other variables. Neither were these results influenced by a relatively small number of subjects who had an abnormal exercise ECG and coronary arteriogram.11
We measured blood pressure noninvasively, which may be less accurate during exercise than invasive measurements18 but is more applicable to routine measurements. The influence of seated blood pressure measurement at rest was not tested. However, we have indications that seated blood pressure measurement at rest would not give additional information: Of the blood pressures measured every other minute during exercise, peak systolic blood pressure at a workload of 600 kpm/min in almost all subjects taken after 6 minutes gave the strongest information, stronger than blood pressure measured after 2 and 4 minutes (data not shown).
Initial workload differed between studies. The initial workload of 600 kpm/min in the present study corresponds fairly well with the initial workload used by Filipovsky et al8 but was higher than in the study of Fagard et al.18 Possibly, an abrupt start of exercise on a fixed, rather high initial workload may explain the clear additional prognostic effect of blood pressure at this load. In this respect, our data may be of greater importance in a physically active population than in a sedentary population.
We can only speculate on the possible mechanisms by which systolic blood pressure during a bicycle ergometer exercise test adds such important prognostic information. In the Framingham Heart Study,19 an increase in cardiac left ventricular mass as assessed by echocardiography predicts a higher incidence of clinical cardiovascular events, including death. There is a significant relation between the level of resting systolic blood pressure and left ventricular mass.20 21 22 The association between left ventricular hypertrophy and exercise blood pressure is more uncertain: Some studies23 24 report similar associations between indexes of left ventricular hypertrophy assessed by echocardiography or electrocardiography and blood pressures measured both at rest and during exercise in hypertensive patients. In one study,25 left ventricular mass was reported to be somewhat better related to systolic pressure at the end of exercise than to resting blood pressure. In other studies,26 27 28 29 significant correlations between left ventricular mass and exercise blood pressure but not blood pressure at rest were observed. Such differences in results between studies20 21 22 23 24 25 26 27 28 29 may be caused by variations in selection of subjects and the methods used.
The question of different methods may be relevant to our finding that maximum blood pressure during exercise did not give any prognostic information.9 One partial explanation for this may be the less standardized and accurate measurements of maximum blood pressure (range for SDs, 17 to 19 mm Hg in the various groups) compared with blood pressure after 6 minutes of exercise at 600 kpm/min (range for SDs, 10 to 17 mm Hg). Possibly, left ventricular dysfunction in some subjects may also induce a fall in blood pressure at high exercise levels and mask a statistical relationship in the overall study.
Echocardiography was not used during the study period from 1972 to 1975, and therefore we cannot rule out the possibility that exercise blood pressure in our study provides additional information on morbidity and mortality through a relationship with left ventricular hypertrophy, although our subjects had normal ECGs. In fact, in a 10-year follow-up study of 280 hypertensive patients, left ventricular hypertrophy detected by echocardiography but not by ECG predicted cardiovascular events, deaths, and all-cause mortality,30 clearly emphasizing the importance of this aspect in hypertensive patients.
Target organ damage is better associated with ambulatory blood pressure
than with casual or clinical blood
pressure.4 5 6 21 31 32 33 34
The prevalence of white coat hypertension, ie, high readings in the
physician's office but normal average blood pressure outside, ranges
from 21% to 58% in various
studies35 36 37 38 39
of
hypertensive subjects depending on how it is defined. In the
present study, 216 of the 520 subjects who had mildly elevated
systolic blood pressure (140 mm Hg) at rest did not increase
their systolic blood pressure to 200 mm Hg at the
standardized initial load during the bicycle ergometer exercise test.
Since these 216 subjects had a normal cardiovascular
death rate of 6%, we9 discussed whether they might have
the white coat phenomenon and hence might not be truly
hypertensive.40 However, from the present data it can
be seen that these subjects have an intermediate risk of morbid events,
although they do not die in excessive numbers during follow-up. If
the white coat phenomenon is present in these subjects, it clearly
is not innocent.
Others41 have found that normotensive persons at high risk of developing systemic hypertension have greater cardiovascular reactivity to physical stress, ie, exaggerated blood pressure response to bicycle exercise. The explanation is a failure to reduce total peripheral resistance during exercise.41 Additionally, one may speculate whether the steep rise in exercise blood pressure signifies a poor arterial compliance and hence represents a pressure response in subjects with more advanced arteriosclerotic diseases or structural vascular changes.42 If so, a rapid rise in exercise blood pressure may be a marker of disease rather than a risk factor for development of disease. Moreover, a very high blood pressure response to a moderate exercise load, such as practiced in everyday life, may further increase the load on both the heart and the vascular system.
It may also be speculated whether a physician should make therapeutic decisions on the basis of epidemiological data such as those provided by the present study. In the debate43 on whether or not to select mildly hypertensive subjects for pharmacological treatment, our data may suggest that an early rise in systolic blood pressure on a standardized initial exercise load during a bicycle test may identify subjects with particularly high risk and make a plea for treatment. In addition, the test itself can be performed easily and requires less resources than, for example, ambulatory 24-hour blood pressure monitoring and echocardiography.
In conclusion, exercise blood pressure is a stronger predictor than casual blood pressure of morbidity and mortality from myocardial infarction, and an early rise of systolic blood pressure during exercise adds prognostic information about mortality from myocardial infarction among otherwise healthy middle-aged men with mildly elevated casual blood pressure. We suggest that blood pressure taken during standardized exercise testing may distinguish between severe and less severe hypertension.
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Acknowledgments |
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This work was supported in part by The Family Blix Foundation.
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Footnotes |
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Reprint requests to Sverre E. Kjeldsen, MD, PhD, Division of Cardiology, Department of Internal Medicine, Ullevaal Hospital, N-0407 Oslo, Norway. E-mail sverrekj@ulrik.uio.no.
Received July 17, 1995; first decision August 15, 1995; accepted November 14, 1995.
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