(Hypertension. 1997;30:1267-1273.)
© 1997 American Heart Association, Inc.
Articles |
Relationship of Tachycardia With High Blood Pressure and Metabolic Abnormalities
A Study With Mixture Analysis in Three Populations
From the Clinica Medica 1, University of Padova, Italy (P. Palatini, E.C., P. Pauletto); the Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Belgium (J.S.); and the Department of Biostatistics (N.K.) and the Division of Hypertension (S.J.), University of Michigan, Ann Arbor.
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Abstract |
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Abstract Faster resting heart rate has been shown to be associated with a higher risk of developing hypertension and a greater incidence of cardiovascular morbidity and mortality. The aim of this study was to investigate the distribution of heart rate and its relationship with blood pressure and other cardiovascular risk factors in three populations. One European general population (Belgian study), one North American general population (Tecumseh study), and one European hypertensive population (HARVEST trial) were studied. Within each population, mixture analysis was used to investigate whether a mixture of two normal distributions explained the variance in heart rate better than a single distribution. In the men of all populations, mixture analysis identified a larger subpopulation of subjects with normal heart rate and a smaller one with fast heart rate. The subgroups with tachycardia had higher blood pressure and lipid levels than those with normal heart rate. In the populations in which they were measured, fasting insulin and postload glucose were also higher in the men with faster heart rate. A subgroup with tachycardia could also be singled out among the women from Tecumseh, but no relation between heart rate and blood pressure could be found. These findings show that in Western societies, high heart rate pertains to a distinct subgroup of subjects, who are more frequently men and exhibit the characteristic features of the insulin resistance syndrome. Sympathetic overactivity is likely to be the mechanism underlying this clinical condition.
Key Words: heart rate • tachycardia • insulin resistance • cardiovascular risk • dyslipidemia • sympathetic system
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There is a body of evidence to demonstrate that elevated resting heart rate is associated with a greater risk of developing sustained hypertension and with increased cardiovascular morbidity and mortality.1 2 3 4 The reason for this association is not clear; it could be related to observations in some studies of an association between tachycardia and other risk factors, such as high blood pressure (BP), smoking, and alcohol consumption.2 3 4 5 6 7 Moreover, it is not well known whether the cardiovascular risk related to heart rate is uniformly distributed across the heart rate range or is peculiar to a subset of the population with "abnormally" high heart rate levels. Another aspect that needs to be clarified is whether the high heart rate reflects an abnormal intrinsic regulation of the pacemaker or whether it is due to the alarm reaction associated with the doctor's visit and other environmental stimuli.
To shed light on this controversial issue, we studied the distribution of heart rate and its relationship with BP and other clinical variables in three white populations. The first purpose of our investigation was to ascertain whether the variation of heart rate in these populations could be explained by a single normal distribution or by a mixture of two distributions. To separate out the two subpopulations, we used univariate mixture analysis, a statistical test devised in the Ann Arbor laboratory.8 If two subpopulations with "normal" and "abnormally" high heart rate could be identified, we studied whether they differed in BP, lipids, postload glucose, and insulin, when available. Finally, in two populations in which 24-hour ambulatory heart rate and BP were recorded, we compared the distribution of clinic heart rate with that of heart rate measured in ambulatory conditions.
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Methods |
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The data sets of three populations studied in different countries were examined (Table 1
). A
North European general population (Belgian),9 a North
American general population (Tecumseh Blood Pressure Study, United
States),10 and a stage I hypertensive population enrolled
in a multicenter Italian study (HARVEST trial)11 were
analyzed. The age of the subjects ranged from 20 to 88 years in
the Belgian population, from 17 to 41 years in the Tecumseh study, and
from 18 to 45 years in the HARVEST trial. Detailed information on the
clinical characteristics of the three populations has been reported at
length elsewhere.9 10 11 12 All studies were approved by the
local institutional review ethical committees, and subjects gave
informed consent. The procedures used in these studies were in
accordance with institutional guidelines.
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BP and heart rate in the three studies were assessed according to the
recommendations of the International Scientific Societies, but the
conditions in which they were measured and the number of readings on
which they were calculated differed from study to study (Table 1
). In
the Tecumseh and the HARVEST studies, BP and heart rate were taken by a
doctor, whereas in the Belgian study, they were measured with an
automatic device (Dinamap, Critikon Co). The number of readings taken
in the three studies varied from two to six (Table 1). BP and heart
rate were measured in the lying position in the HARVEST study and in
the sitting position in the other two studies.
In the Belgian and HARVEST studies, BP and heart rate were recorded also by means of 24-hour ambulatory monitoring. In both studies, only devices validated according to the British Hypertension Society13 and the Association for the Advancement of Medical Instrumentation14 recommendations were used. The methods used in the application of the instrumentations and the analysis of the recordings have been reported extensively elsewhere.15 16
Medical history and anthropometric data were taken in all studies, and fasting blood specimens were drawn for routine biochemistry. In the Belgian study, serum glucose was determined also, after a 75-g glucose load, and in the Tecumseh study, fasting insulin was measured. Other details on the methods used in the studies have been published previously.9 10 11 12
Statistical Analysis
The independent association of heart rate with BP in the three
populations was studied with multiple forward stepwise regression
analysis, using BP as the dependent variable and heart
rate, age, body mass index (BMI), smoking, alcohol intake, and physical
activity habits as independent variables.
The distribution of heart rate in the populations stratified by sex was
assessed with the Shapiro-Wilk's test, and if a nonnormal distribution
was present, data were inspected with the Q-Q plot. The Q-Q plot
plots empirical quantiles against theoretical quantiles for normal
distribution.17 When the distribution of the variable
under examination has the same shape as the reference distribution, the
Q-Q plot is linear (Fig 1c). When the
distribution is skewed and/or the kurtosis is different from 0, one or
both ends of the plot deflect from the reference line (Fig 1a). To
determine more objectively when the pattern of points deviates from the
comparison line, 95% confidence limits for the normal Q-Q plot can be
estimated.17 For better visual inspection, plots were
subsequently untilted, by subtracting the values of the comparison line
from the data points.18 With this approach, departures
from the reference value are easier to see (Fig 1b and 1d).
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In the populations in which the heart rate distribution was skewed, we used univariate mixture analysis to determine whether the apparently heterogeneous population was composed of more than one homogeneous normal subpopulation.8 Mixture analysis is a technique used in the biological sciences to investigate the likelihood that a mixture of normal distributions better explains the variation of a trait than a single distribution. Typically, overlap between the subpopulations results in observations that can be classified into any one of the groups. Individuals were assigned to the two subpopulations by a classification rule based on a likelihood that minimized the expected total number of misclassifications and allowed identification of a reliable cutoff level between the two groups. In the populations in which the two subpopulations differed by age and BMI, a subsequent mixture analysis was generated after adjusting for the aforementioned variables. Further details on this statistical procedure have been published elsewhere.19
Comparisons between subgroups were performed by Student's t
test for continuous variables and by 
2 for
categorical ones. In the subpopulations in which age, BMI, smoking,
alcohol intake, and physical activity were significantly different, a
general linear model procedure was used to calculate BP levels and
biochemical parameters adjusted for the above-mentioned
confounders.
Data are expressed as mean±SEM, unless specified otherwise. Significance was accepted at P<.05.
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Results |
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In all populations, mean heart rate was higher in the women than in the men and lower in the Belgian population, in which it had been measured with an automatic device (Table 1
). BMI was similar in the
three populations and was greater in the male sex.
Regression Analyses
To assess the association of heart rate with systolic BP,
diastolic BP, and mean BP, a series of
multivariate regression analyses was performed
(see "Methods" for the model). For brevity, only the results for
mean BP are reported (Table 2). In all
populations, heart rate turned out to be a significant independent
predictor of BP in both men and women. However, the BP/heart rate
association was much stronger in the men than the women. In the men,
heart rate explained 10%, 12.2%, and 4.9% of the variance in mean BP
in the Belgian, Tecumseh, and HARVEST populations, respectively. The
corresponding values for the women were 3.1%, 3.8%, and 4.3%,
respectively.
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In the Belgian and HARVEST populations, the relationship of 24-hour BP with 24-hour heart rate could also be studied. In both studies, the BP/heart rate association was weaker for 24-hour than for clinic measurement.
Distribution of Heart Rate in the Populations
In the men of the three populations, clinic heart rate
distribution was nonnormal (P<.0001 according to the
Shapiro-Wilk's test), with positive coefficients of skewness in all
studies (range, .57 to .82). In the women, heart rate was nonnormally
distributed only in the Tecumseh population (P<.0001), with
a coefficient of skewness of .49, and was normally distributed in the
Belgian and HARVEST studies.
The heart rate Q-Q plot was linear in the women of the Belgian and
HARVEST populations. On the contrary, a clear departure from the upper
end of the reference (normal) line toward higher values of heart rate
was observed in the men of the three populations and the women from
Tecumseh. The findings for the HARVEST population are illustrated in
Fig 1.
In both the Belgian and HARVEST studies, 24-hour heart rate recorded outside the hospital showed a normal distribution.
Classification by Mixture Analysis
In the men and women in whom the Q-Q plot showed a skewed
distribution, the mixture analysis identified two subgroups. In
Fig 2 the results related to the Tecumseh
population are reported. In all populations, the larger group had lower
values of heart rate ("normal" heart rate) and the smaller group
had higher values ("high" heart rate). After classification, with
the use of the test discussed in Schork and Schork,19 we
could reject the hypothesis of a single skewed distribution in favor of
a mixture of two distributions (all P<.0001).
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The heart rate cutoff point between the two subpopulations varied from
population to population and within the Tecumseh population was
slightly higher in the female sex (Table 3). As expected, in the males, the lowest
cutoff value was found in the Belgian study. The percentage of male
subjects with high heart rate ranged from 8.4% (Belgian population) to
19.3% (Tecumseh population).
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Age, BMI, and Lifestyle Factors by Heart Rate Group
In the HARVEST study, age tended to be lower in the subjects with
high heart rate (Table 3). In the Belgian men, BMI was greater among
the subjects with high heart rate. No significant differences in BMI
were found in the other two populations. Men with high heart rate were
more sedentary than those with normal heart rate in the HARVEST study
(P=.004). No significant differences in smoking or alcohol
consumption were found according to heart rate levels.
Belgian and HARVEST men with tachycardia on the basis of clinic measurement also had higher values of ambulatory heart rate compared with subjects with normal clinic heart rate. Average 24-hour heart rate was 78.4±1.9 beats per minute (bpm) in the Belgian males with high clinic heart rate and 70.0±0.4 bpm in those with normal heart rate (P<.0001). The corresponding values for the HARVEST males were 76.5±0.8 bpm and 70.5±0.3 bpm, respectively (P<.0001).
BP and Results of Blood Tests by Heart Rate Group
In Table 4, BP adjusted for
confounders (see "Methods") in the subjects with normal heart
rate and high heart rate is shown. In the men of all populations, both
systolic and diastolic BPs were higher in the
subjects with high heart rate. The between-group difference in
diastolic BP failed to reach the level of statistical
significance in the HARVEST population. No BP differences according to
heart rate levels were found in the women from Tecumseh.
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Among the men, total cholesterol and triglycerides adjusted for confounders (see "Methods") were more elevated in the subjects with high heart rate than in those with normal heart rate. The differences were significant in the Tecumseh (4.8±0.1 mmol/L versus 4.6±0.04 mmol/L; P=.03) and HARVEST (5.3±0.1 mmol/L versus 5.1±0.03 mmol/L; P=.02) studies for cholesterol and in the Belgian population for triglycerides (4.2±0.5 mmol/L versus 3.1±0.1 mmol/L; P=.04). No heart rate–related differences in lipids were found in the women from Tecumseh.
Within the Belgian men, postload glucose proved to be much higher in
the subjects with high heart rate than in those with normal heart rate,
being 5.9±0.2 mmol/L in the former and 5.0±0.1
mmol/L in the latter (P<.0001). Similar results were
obtained for fasting insulin in the Tecumseh study (Fig 3): In the subjects with high heart rate,
insulin was significantly increased in comparison with those with
normal heart rate. The difference was greater in the male sex.
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Discussion |
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Previous studies have demonstrated that resting clinic heart rate is an independent risk factor for adult cardiovascular disease in general and coronary heart disease in particular.1 2 3 4 However, the pathogenesis of the connection between elevated heart rate and cardiovascular disease remains obscure. A number of mechanisms for this association have been postulated. Data from animal models suggest that the atherogenic action of high heart rate may be related to its effects on blood flow characteristics, which would favor the occurrence of arterial wall lesions.20 21 According to some authors, tachycardia may merely indicate poor physiological fitness and/or subclinical loss of cardiac reserve.3 4 Moreover, it has been postulated that elevated heart rate may reflect a higher consumption of tobacco or alcohol,3 4 which are well-recognized risk factors for cardiovascular disease. A portion of the effect on coronary heart disease has been attributed to high BP, which appeared consistently positively correlated with pulse rate in several studies,5 6 7 but the nature of this relationship remains unclear.
Methodological Issues
In the present study, the relationship between heart rate and
BP has been assessed through the analysis of three populations.
To assess whether differences in lifestyle habits could influence the
relationship of tachycardia with hypertension and other
cardiovascular risk factors, we studied two Western
general populations from different geographic areas.9 10
The analysis of the HARVEST dataset11 allowed us
to investigate whether the relationship between
tachycardia, increased BP, and metabolic
abnormalities held true also in a hypertensive population and to
compare the results of clinic measurements with those obtained by
24-hour recordings.
The statistical analysis of these populations permitted us to detect whether underlying factors can have a small effect (microphenic factors) or a large one (megaphenic factors) on the overall distribution of the heart rate.22 Most quantitative traits such as heart rate are affected only by microphenic factors, which can be the product of the individual genome, environmental influences, and their interaction.22 Megaphenic factors are rare, but when present, they tend to displace the average value of the affected subgroup from the average value of those people who are not affected. In this case, a mixture of two distributions is likely to explain the variation in the trait better than a single distribution. As the distribution of heart rate in most of our subjects was skewed, we wanted to ascertain whether the skewness resulted from the existence of two statistically separate populations. To do so, we used univariate mixture analysis, which is an entirely objective way to detect the existence of more than one homogeneous subpopulation within an apparently heterogeneous population.8
Prevalence and Clinical Significance of Tachycardia
In this study, we found a close correlation between BP and heart
rate in all populations, and the relationship persisted after
adjustment for other factors potentially influencing heart rate. The
association was stronger in the male sex. However, it should be pointed
out that heart rate explained only a small fraction of the variance in
BP (4.9% to 12.2% in the men). Thus, although the heart rate/BP
association appears to be strong from a statistical standpoint, the
clinical relevance of this association is minimal. On the other hand,
mixture analysis showed that in the men across all populations,
this association was mostly explained by a subpopulation of subjects
with "high" heart rate who had higher levels of BP. The
percentage of male subjects with tachycardia varied from
8.4% to 19.3%. Among the women, a separation between subjects with
high and normal heart rate could be found only in the Tecumseh study,
but no BP difference was observed between the two subpopulations. A
sex-related difference in the association between heart rate and BP was
previously reported by other authors.2 5
Another interesting finding of the present analysis is that men with tachycardia also had high values of cholesterol and triglycerides, high fasting insulin, and increased postload glucose, which are characteristic features of the insulin resistance syndrome.23 This may explain why subjects with elevated heart rate develop sustained hypertension in later life, as documented by prospective studies conducted in either young24 or adult individuals.1 25 A higher BP, overweight, and disturbances of the glucose metabolism are all well-known risk factors for future hypertension. The clustering of these risk factors together with dyslipidemia, referred to as syndrome X,23 found in the present analysis in the subpopulations with high heart rate may explain why cardiovascular morbidity is higher in individuals with tachycardia.
Since in this study we argue that one main determinant of heart rate
distribution in the general population is a megaphenetic factor, it
seems appropriate to discuss the nature of this factor and to attempt
to clarify the pathophysiological relationship
between tachycardia, hypertension, and the
metabolic abnormalities. As mentioned above, in all male
populations, we found a skewed distribution of clinic heart rate and a
highly significant correlation between clinic heart rate and clinic BP.
When we studied heart rate and BP measured outside the hospital in
ambulatory conditions, heart rate did not show a skewed distribution,
and its association with BP was weaker. It is known that BP and heart
rate measured in the clinic in part reflect the alarm reaction to the
doctor, which may greatly vary from individual to
individual.26 Furthermore, it has been demonstrated that
BP and heart rate vary directionally in the same manner in response to
daily life stressors, suggesting that central influences act
consensually on the heart and the arterioles.27 Overall,
these findings indicate that the sympathetic nervous system plays a
major role in controlling heart rate and BP and suggest that in the
subgroups of subjects identified as having tachycardia by
mixture analysis, sympathetic overactivity is operative. If one
assumes that tachycardia is a marker of abnormal autonomic
control, it is easier to understand why it is associated with the
classical features of the insulin resistance syndrome and why in the
long run it can lead to atherosclerosis and its
complications. In fact, it has been shown that sympathetic overactivity
may cause insulin resistance through both 
and ß stimulation.
Vasoconstriction mediated by -adrenergic receptors appears to impair
the ability of skeletal muscles to use glucose,28 and
-adrenergic blockade has been shown to improve insulin
sensitivity.29 Acute stimulation of ß-receptors with
epinephrine infusion causes insulin resistance that can be
reversed by propranolol.30 Also, chronic
ß-adrenergic stimulation can lead to insulin resistance, through the
conversion from a small to a larger proportion of
insulin-resistant fast-twitch fibers in skeletal
muscles.31 The relationship between
hyperinsulinemia and lipid abnormalities has long
been recognized, and the mechanisms responsible for this association
have been elucidated.23
Clinical Implications
The interrelationship between heart rate, BP, and
metabolic abnormalities shown by the present
analysis in men suggests that although tachycardia
may reflect a short-term emotional response to the conditions of
measurement, it should not be regarded as being innocuous. Several
lines of evidence suggest that the so-called white-coat phenomenon is
associated with a greater frequency of target organ damage in
hypertension.10 15 32 Thus, the data of the present
study call for revision of attitudes toward subjects with high heart
rates at clinic examination and suggest that those individuals should
not be dismissed as simply being "nervous." However, we could not
provide a general partition value to distinguish between subjects with
normal and high heart rate.
The threshold value between tachycardia and normal heart rate identified by mixture analysis varied from 75 to 85 bpm in the three populations. These differences stem from the variability in the measurement of heart rate. In fact, the cutoff point was lower (75 bpm) in the Belgian population, in which an automatic device was used, thereby avoiding the psychological stress related to the presence of the doctor. The International Scientific Societies have established strict rules for the measurement of BP, whereas no specific recommendations have been provided for the assessment of heart rate. And yet, sources of variability are more common with the measurement of heart rate, which can be substantially influenced by the method employed (ECG versus pulse rate) or the position of the body. The calculation of heart rate may be affected also by the number of measurements, which varied from two to six in our populations, the length of resting time before the measurement(s), or the time of the day in which heart rate is measured.
In the present study, we provided substantial evidence for the clinical importance of tachycardia, which should be regarded by clinicians as an important risk factor for cardiovascular diseases. To establish what heart rate levels should be considered hazardous, the methods used to measure heart rate should be carefully standardized in future studies.
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Footnotes |
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Reprints requests to Prof Paolo Palatini, MD, Clinica Medica 1, University of Padova, via Giustiniani, 2, 35126 Padova, Italy.
Received March 25, 1997; first decision April 29, 1997; accepted May 8, 1997.
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 G. Mancia, R. Facchetti, M. Bombelli, H. P. Friz, G. Grassi, C. Giannattasio, and R. Sega Relationship of Office, Home, and Ambulatory Blood Pressure to Blood Glucose and Lipid Variables in the PAMELA Population Hypertension, June 1, 2005; 45(6): 1072 - 1077. [Abstract] [Full Text] [PDF]
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A. Diaz, M. G. Bourassa, M.-C. Guertin, and J.-C. Tardif Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease Eur. Heart J., May 2, 2005; 26(10): 967 - 974. [Abstract] [Full Text] [PDF]
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 P. M. Nilsson, M. Roost, G. Engstrom, B. Hedblad, and G. Berglund Incidence of Diabetes in Middle-Aged Men Is Related to Sleep Disturbances Diabetes Care, October 1, 2004; 27(10): 2464 - 2469. [Abstract] [Full Text] [PDF]
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L. J. Martin, A. G. Comuzzie, G. E. Sonnenberg, J. Myklebust, R. James, J. Marks, J. Blangero, and A. H. Kissebah Major Quantitative Trait Locus for Resting Heart Rate Maps to a Region on Chromosome 4 Hypertension, May 1, 2004; 43(5): 1146 - 1151. [Abstract] [Full Text] [PDF]
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T. Kazumi, A. Kawaguchi, K. Sakai, T. Hirano, and G. Yoshino Young Men With High-Normal Blood Pressure Have Lower Serum Adiponectin, Smaller LDL Size, and Higher Elevated Heart Rate Than Those With Optimal Blood Pressure Diabetes Care, June 1, 2002; 25(6): 971 - 976. [Abstract] [Full Text] [PDF]
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F Thomas, K Bean, L Guize, S Quentzel, P Argyriadis, and A Benetos Combined effects of systolic blood pressure and serum cholesterol on cardiovascular mortality in young (<55 years) men and women Eur. Heart J., April 1, 2002; 23(7): 528 - 535. [Abstract] [Full Text] [PDF]
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 L. A. Colangelo, S. M. Gapstur, P. H. Gann, A. R. Dyer, and K. Liu Colorectal Cancer Mortality and Factors Related to the Insulin Resistance Syndrome Cancer Epidemiol. Biomarkers Prev., April 1, 2002; 11(4): 385 - 391. [Abstract] [Full Text] [PDF]
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 F. Seccareccia, F. Pannozzo, F. Dima, A. Minoprio, A. Menditto, C. Lo Noce, and S. Giampaoli Heart Rate as a Predictor of Mortality: The MATISS Project Am J Public Health, August 1, 2001; 91(8): 1258 - 1263. [Abstract] [Full Text] [PDF]
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 T. Y. Wong, S. E Moss, R. Klein, and B. E K Klein Is the pulse rate useful in assessing risk of diabetic retinopathy and macular oedema? The Wisconsin Epidemiological Study of Diabetic Retinopathy Br J Ophthalmol, August 1, 2001; 85(8): 925 - 927. [Abstract] [Full Text] [PDF]
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S. Julius, M. Valentini, and P. Palatini Overweight and Hypertension : A 2-Way Street? Hypertension, March 1, 2000; 35(3): 807 - 813. [Abstract] [Full Text] [PDF]
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 K. Narkiewicz and V. K. Somers Interactive Effect of Heart Rate and Muscle Sympathetic Nerve Activity on Blood Pressure Circulation, December 21, 1999; 100(25): 2514 - 2518. [Abstract] [Full Text] [PDF]
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 P. Palatini, E. Casiglia, S. Julius, and A. C. Pessina High Heart Rate: A Risk Factor for Cardiovascular Death in Elderly Men Arch Intern Med, March 22, 1999; 159(6): 585 - 592. [Abstract] [Full Text] [PDF]
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P. Palatini, O. Vriz, S. Nesbitt, J. Amerena, S. Majahalme, M. Valentini, and S. Julius Parental Hyperdynamic Circulation Predicts Insulin Resistance in Offspring : The Tecumseh Offspring Study Hypertension, March 1, 1999; 33(3): 769 - 774. [Abstract] [Full Text] [PDF]
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P. Palatini Need for a Revision of the Normal Limits of Resting Heart Rate Hypertension, February 1, 1999; 33(2): 622 - 625. [Full Text] [PDF]
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