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(Circulation. 1997;96:897-903.)
© 1997 American Heart Association, Inc.
Articles |
Association of Cigarette Smoking With Chronotropic Incompetence and Prognosis in the Framingham Heart Study
From the Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio (M.S.L., F.J.P.); Department of Preventive Medicine and Epidemiology, Boston University, Boston, Mass (M.G.L., D.L.); The Framingham Heart Study, Framingham, Mass (M.G.L.); and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (D.L.).
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Abstract |
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Background In this study, we sought to determine whether cigarette smoking is associated with chronotropic incompetence and to explore prognostic implications of this association.
Methods and Results Members of the Framingham Offspring Study (1468 men and 1642 women) underwent graded exercise. Chronotropic incompetence was assessed in two ways: (1) failure to achieve an age-predicted target heart rate and (2) a low chronotropic index, a heart rate response measure that accounts for effects of age, resting heart rate, and physical fitness. Smokers were more likely to fail to reach target heart rate than were nonsmokers (men, 25% versus 15%, odds ratio [OR], 1.97; 95% confidence interval [CI], 1.51 to 2.56; women, 32% versus 18%; OR, 2.10; 95% CI, 1.63 to 2.61) and were more likely to have a low chronotropic index (men, 17% versus 12%; OR, 1.50; 95% CI, 1.12 to 2.03; women, 17% versus 8%; OR, 2.28; 95% CI, 1.68 to 3.09). These associations persisted after adjustment for age, cardiovascular risk factors, pulmonary function, and ST-segment response to graded exercise. During 8 years of follow-up, there were 48 deaths and 90 incident coronary heart disease events among the men. After adjustment for the same confounders, men who were smokers and failed to achieve target heart rate were at particularly high risk for death (adjusted relative risk [RR], 2.45; 95% CI, 1.14 to 5.24) and for coronary heart disease (adjusted RR, 4.92; 95% CI, 2.84 to 8.53). There were too few end points in women for analysis.
Conclusions In this population-based cohort, cigarette smoking was predictive of chronotropic incompetence. Male smokers who manifested chronotropic incompetence were at particularly high risk for death and coronary heart disease events.
Key Words: heart rate • exercise • epidemiology • prognosis • smoking
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Introduction |
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An attenuated heart rate response to exercise, or chronotropic incompetence, has been shown to be predictive of all-cause mortality and coronary heart disease risk, even after taking into account the effects of age, physical fitness, and resting heart rate.1 2 Previous authors have reported that cigarette smoking is associated with a decreased heart rate response to exercise among otherwise healthy men,3 but they have not determined whether this association persists after accounting for age, body weight, physical fitness, and other potential confounders. Furthermore, there are few data regarding smoking and chronotropic response to exercise among women.
The purpose of this study was to extend on previously published work by investigating in detail the association between cigarette smoking and chronotropic incompetence in a healthy, population-based cohort of primarily middle-aged men and women. This study also sought to investigate the separate and combined prognostic relations of these two factors to incident coronary heart disease and all-cause mortality.
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Methods |
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Population Sample
The Framingham Heart Study was started in 1948 as a population-based epidemiological investigation of heart disease.4 5 In the early 1970s, offspring and spouses of offspring were enrolled in the Framingham Offspring Study.6 As part of their second examination (performed between 1979 and 1983), participants in the Offspring Study underwent a detailed evaluation, which included pulmonary spirometry, exercise testing according to the Bruce protocol,7 and blood tests. All subjects gave informed consent before the examination.
To be eligible for this study, subjects had to reach stage 2 of the Bruce protocol; exclusion criteria included use of ß-blockers or digitalis preparations, atrial fibrillation, bundle-branch block, preexcitation pattern on the resting ECG, other baseline ST abnormalities that would preclude interpretation of ST-segment changes with exercise, chronic obstructive pulmonary disease, congestive heart failure, existing coronary heart disease, and valve disease.
Clinical Data
Subjects were questioned in detail about current and prior
cigarette smoking habits. Subjects were also queried on usual levels of
physical activity, from which a physical activity index was
calculated.8
Physical examination included two physician-obtained blood pressure measurements that were averaged. Height and weight were directly measured; obesity was assessed using the body mass index (weight in kilograms divided by height squared in meters). Spirometry included measurement of FEV1 and FVC.
Subjects were considered to have significant chronic obstructive
pulmonary disease if they had a ratio of FEV1 to
FVC of <0.7 and the examining physician had a clinical impression that
chronic lung disease was present. Subjects were considered to have
hypertension if they had a resting systolic blood pressure
140 mm Hg or a resting diastolic blood pressure
90 mm Hg, or they were currently using antihypertensive
medication.9 Diabetes was defined on the basis of use of
insulin or oral hypoglycemic agents or a fasting blood glucose of 140
mg/dL (7.77 mmol/L) at the index examination.
Criteria for diagnoses of congestive heart failure, coronary
disease, and valvular heart disease have been previously
described in detail.10
Exercise Testing
Graded exercise testing was performed according to the Bruce
protocol with testing terminated if a subject achieved a target heart
rate (based on 85% of the age-predicted maximum heart
rate),11 requested stopping, or developed symptoms (eg,
severe chest pain, fatigue, leg discomfort, dyspnea), frequent
premature ventricular beats, >2 mm of
ischemic ST-segment depression, or a systolic blood
pressure of >250 mm Hg. Heart rate and blood pressure were
measured at rest and 90 seconds into each stage of exercise. Exercise
capacity expressed in METs was estimated using previously published
tables.12 An ischemic ST-segment response was
defined as the occurrence of an additional (over baseline) 0.10 mV
(1.0 mm) or more of horizontal or downsloping ST-segment
depression measured 80 ms after the J-point.
Follow-up
Subjects were followed for an average of 8 years. Clinical end
points included all-cause mortality and coronary heart disease
events, including new-onset angina pectoris, coronary
insufficiency, myocardial infarction, and sudden and nonsudden cardiac
death. Definition of outcome events and methods of ascertainment have
been previously described in detail.10
Statistical Analyses
All analyses were gender specific. For analyses
of baseline and exercise characteristics, subjects were divided into
three groups: never smokers, ex-smokers, and current smokers.
Comparisons among groups on continuous variables were made with
ANOVA; comparisons on categorical variables were performed with the
2 test.
Chronotropic incompetence was first assessed as failure to achieve target heart rate.11 This method may be confounded by effects of age, physical fitness, and resting heart rate, so chronotropic response was also assessed by calculating the ratio of heart rate reserve used to metabolic reserve used at stage 2 of exercise; this "chronotropic index" has been previously described in detail.13 Briefly, for any given stage of exercise, the percent metabolic reserve (MR) used is: %MR used=[(METsstage -METsrest)/(METspeak - METsrest)]x100.
In an analogous fashion, for the percent heart rate reserve (HRR) used is: %HRR used=[(HRstage - HRrest)/(220 - age - HRrest)]x100.
In a group of healthy, nonhospitalized adults, the ratio of percent
heart rate reserve used to percent metabolic reserve used
exercise was 
1 (95% CI, 0.8 to 1.3).13 Thus,
chronotropic incompetence can be defined as a percent heart rate
reserve used–to–percent metabolic reserve used ratio at
stage 2 of exercise of <0.8; this will be referred to as a low
chronotropic index. The advantage of using this approach to assess
chronotropic response is that it accounts for age, functional capacity,
and resting heart rate13 ; it is not merely a reflection of
physical fitness or exercise time.
ORs were calculated for failure to achieve target heart rate and for
low chronotropic index as a function of current smoking status. Similar
analyses were performed for subgroups based on age (<40, 40 to
54, and 55 years), body mass index (<23, 23 to 25.99, 26 to 29.99,
and 30 kg/m2), use of antihypertensive
medications, and physical activity index (above or below sex-specific
median values). Adjusted ORs based on these strata were calculated
using the Cochran-Mantel-Haenszel method. Logistic regression
analyses14 related current smoking to heart rate
responses after adjustment for age, body mass index, blood pressure,
use of antihypertensive medications, physical activity index, diabetes,
ratio of total to HDL cholesterol, ratio of
FEV1 to FVC, and ST-segment changes with exercise. To
determine whether a dose-response relationship exists between smoking
and chronotropic incompetence, similar supplementary analyses
were restricted to current smokers.
Associations of failure to achieve target heart rate and low chronotropic index with all-cause mortality and incident coronary heart disease were examined separately for smokers and nonsmokers. These outcome analyses were restricted to men because of the very small numbers of events among women (16 deaths and 22 incident coronary heart disease events). For each chronotropic variable, subjects were divided into four groups according to smoking status (smoker/nonsmoker) and chronotropic response (normal/abnormal). Cumulative incidence curves were calculated in each group using the Kaplan-Meier product-limit method. Cox proportional hazards analyses15 were performed relating time free of outcome events to smoking and chronotropic incompetence combined after adjustment for age, body mass index, blood pressure, use of antihypertensive medications, physical activity index, diabetes, ratio of total to HDL cholesterol, ratio of FEV1 to FVC, and ST-segment response to exercise.
All analyses were performed using Version 6.09 of the SAS statistical package16 on a Sun Sparc2 workstation.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Baseline and Exercise Characteristics
There were 1690 men and 1838 women who were potentially eligible for analyses. Among men, major reasons for exclusion included chronic obstructive pulmonary disease (64, 3.8%), abnormal ST-segments at rest (55, 3.3%), existing coronary heart disease (54, 3.2%), ß-blocker use (46, 2.7%), and failure to complete stage 2 of exercise (30, 1.8%); among women, major reasons for exclusion included failure to complete stage 2 of exercise (65, 3.6%), ß-blocker use (49, 2.7%), abnormal ST-segments at rest (41, 2.2%), and chronic obstructive pulmonary disease (35, 1.9%).
There were 1468 men and 1642 women eligible for analyses; 599
men (41%) and 572 women (35%) were current smokers. Gender-specific
baseline characteristics according to smoking status are summarized in
Table 1
. Male smokers starting smoking at
a mean age of 17±4 years, smoked an average of 21±16 cigarettes a
day, and had an average 28±22 pack-year smoking history; 174 (29%)
smoked <10 cigarettes per day, 198 (33%) smoked from 10 to 20
cigarettes per day, and 227 (38%) smoked >20 cigarettes per day.
Female smokers starting smoking at a mean age of 19±5 years, smoked an
average of 20±12 cigarettes a day, and had an average 23±18 pack-year
smoking history; 118 (21%) smoked <10 cigarettes per day, 271 (47%)
smoked from 10 to 20 cigarettes per day, and 183 (32%) smoked >20
cigarettes per day.
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Gender-specific exercise characteristics as a function of smoking
status are summarized in Table 2. Heart
rates at stage 2 of exercise (which, by definition, all subjects had to
achieve) as a function of age and smoking status are shown in Fig 1; with the exception of men under age
40, smoking was consistently associated with a significantly
lower stage 2 heart rate.
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Failure to achieve target heart rate was observed in 280 men (19%) and 379 women (23%); a chronotropic index of <0.8 occurred in 200 men (14%) and 189 women (12%). Among men who failed to achieve target heart rate, reasons for termination included leg discomfort (66, 24%), dyspnea (65, 24%), fatigue (46, 16%), ischemic ST-segments (22, 8%), excessive increase in systolic blood pressure (6, 2%), participant request (5, 2%), and frequent ventricular ectopy (4, 1%). Among women who failed to achieve target heart rate, reasons for termination included dyspnea (103, 27%), leg discomfort (90, 24%), fatigue (82, 22%), participant request (31, 8%), and ischemic ST-segments (10, 3%).
Smoking and Chronotropic Incompetence
Rates of failure to achieve target heart rate and low chronotropic
index according to smoking status are shown in Fig 2; current smokers were more likely to
manifest chronotropic incompetence by both measures than were
never-smokers or ex-smokers. Because the major differences were noted
between current smokers and current nonsmokers (combining never and
ex-smokers), all further comparisons were made between current smokers
and current nonsmokers.
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Among men, 25% of smokers failed to reach their target heart rate
compared with 15% of nonsmokers (OR, 1.97; 95% CI, 1.51 to 2.56);
among women, 32% of smokers failed to reach their target heart rate
versus 18% of nonsmokers (OR, 2.10; 95% CI, 1.63 to 2.61). Low
chronotropic index occurred in 17% of male smokers compared with 12%
of male nonsmokers (OR, 1.50; 95% CI, 1.12 to 2.03); among women, low
chronotropic index occurred in 17% of smokers and 8% of nonsmokers
(OR, 2.28; 95% CI, 1.68 to 3.09). Smoking remained associated with a
failure to achieve target heart rate and with a low chronotropic index
after stratifying for age, body mass index, use of antihypertensive
medications, and physical activity index (Table 3).
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Multivariable Analyses
After adjustment for age, body mass index, blood pressure, use of
antihypertensive medications, physical activity index, diabetes, ratio
of total to HDL cholesterol, ratio of FEV1 to
FVC, and ST-segment response, smoking remained associated with failure
to achieve target heart rate in men (adjusted OR, 2.55; 95% CI, 1.90
to 3.43) and in women (adjusted OR, 2.64; 95% CI, 2.01 to 3.47).
Similarly, smoking remained associated with a low chronotropic index in
men (adjusted OR, 1.54; 95% CI, 1.13 to 2.09) and in women (adjusted
OR, 2.89; 95% CI, 2.04 to 4.09). No evidence of significant
interactions was noted between smoking and age, body mass index, or
antihypertensive medication.
Impact of Average Daily Number of Cigarettes Smoked
Among current smokers, a higher average daily number of cigarettes
smoked was associated with chronotropic impairment (Fig 3). Male smokers who smoked 10
cigarettes per day were more likely to fail to achieve target heart
rate (OR, 2.40; 95% CI, 1.51 to 3.82) and to have a low chronotropic
index (OR, 1.64; 95% CI, 0.98 to 2.75); similarly, female smokers who
smoked 10 cigarettes per day were more likely to fail to achieve
target heat rate (OR, 1.85; 95% CI, 1.15 to 2.98) and to have a low
chronotropic index (OR, 2.09; 95% CI, 1.10 to 3.98). Adjustment for
potential confounders in multivariable logistic regression
analyses had no substantial impact on this association.
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Smoking, Chronotropic Incompetence, and Outcome
During 8 years of follow-up of the men, there were 48 deaths.
There were 90 men with incident coronary disease events,
including 44 with myocardial infarction, 38 with a new episode of
angina pectoris, 3 with coronary insufficiency, and 5 sudden
cardiac deaths. When subjects were cross-classified by smoking and
chronotropic response, those who both smoked and had impaired
chronotropy had markedly higher rates of all-cause mortality and
incident coronary heart disease (Tables 4 and 5).
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Although smokers with normal chronotropic responses were at increased risk for events, smokers who also failed to achieve their target heart rate or had a low chronotropic index had markedly increased hazards for death and coronary heart disease (eg, hazard ratios of 5.84 and 4.59, respectively, when using chronotropic index as the measure of heart rate response). Interactions terms considering both smoking and chronotropic responses together showed no evidence of a synergistic effect.
In supplementary analyses, we explored the impact of specific causes of test termination among those subjects who failed to achieve their target heart rate on all-cause mortality and incident coronary heart disease. Dyspnea, fatigue, and leg discomfort were not related to all-cause mortality after adjustment for age and smoking status. However, incident coronary heart disease was associated with test-terminating dyspnea (adjusted RR, 1.41; 95% CI, 1.05 to 1.90), fatigue (adjusted RR, 1.66; 95% CI, 1.20 to 2.29), and leg discomfort (adjusted RR, 1.57, 1.16 to 2.13).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Principal Findings
In a population-based cohort of healthy, primarily middle-aged adults, cigarette smoking was associated with chronotropic incompetence, whether assessed by failure to achieve target heart rate or by a low chronotropic index. Among current smokers, a dose-response relation was noted in which those who smoked more cigarettes per day were more likely to manifest abnormal chronotropic responses. In the models of time to death and coronary heart disease events, smoking and chronotropic response have multiplicative effects on risk in men; smokers who manifest chronotropic incompetence represent a particularly high-risk subset.
Smoking-Associated Exercise Abnormalities
Previous groups have described impaired exercise tolerance and
abnormal heart rate responses among cigarette smokers. Gordon and
colleagues3 studied 6238 asymptomatic men in
the Lipid Research Clinics Coronary Prevention Trial who
underwent submaximal treadmill testing. Smokers were nearly twice as
likely to stop exercise primarily due to fatigue, dyspnea, or leg pain,
even after adjustment for standard risk factors; they also had blunted
heart rate responses to exercise. Similar findings have been reported
in young men enrolled in the CARDIA Study,17 in 586 males
of the Indiana State Police force,18 and in 3045 Navy
personnel.19
The present study expands on these findings in four important respects. First, smoking was associated with chronotropic incompetence both by the traditional measure of failure to achieve an age-predicted target heart rate and by the more recently described chronotropic index.13 The chronotropic index takes into account the effects of age, physical fitness, and resting heart rate; it is independent of protocol and allows for assessment of heart rate changes during early, and not just late, exercise.13 Furthermore, the chronotropic index has been shown to be predictive of prognosis.1 Thus, the association between smoking and chronotropic incompetence is not just a reflection of impaired exercise capacity. Second, the associations between smoking and the two measures of chronotropic incompetence persisted after accounting for a number of potential confounders. Third, the present study included women as well as men. Fourth, follow-up over 8 years demonstrated that male smokers who manifested chronotropic incompetence were at particularly high risk for death and coronary heart disease.
Mechanisms
The mechanisms by which cigarette smoking is associated with
chronotropic impairment are unclear. Smoking is associated with a
number of adverse cardiopulmonary changes, including
coronary vasoconstriction,20 abnormal
coronary endothelial function,21
increased ischemic burden,22 increased
peripheral vascular resistance,23 and
subclinical pulmonary disease.24 None of these
effects clearly explains the association between smoking and an
impaired chronotropic response.
One possible mechanism by which smoking might lead to chronotropic incompetence would be via modulation of chronic autonomic tone. The association between smoking and autonomic function was recently demonstrated in a study showing that smokers who quit manifest improvements in heart rate variability.25 Smoking acutely raises resting heart rate and blood pressure26 and is associated with enhanced local norepinephrine and epinephrine release27 ; thus, autonomic tone within the cardiac conduction system may be effectively increased despite the absence of increased circulating catecholamine levels.27 Increased sympathetic tone has been shown to be associated in turn with impaired heart rate responses to exercise,28 perhaps due to downregulation of ß-adrenergic receptors. Further studies will be needed to determine whether this or other mechanisms can account for the association between smoking and impaired chronotropy.
Limitations
The Framingham Heart Study sample population is overwhelmingly
white, and therefore the current results may not apply to nonwhite
populations. Exercise tests were submaximal, based on achievement of
target heart rate, and not symptom limited. The use of an incremental
protocol may also lead to overestimation of exercise
capacity.29 Finally, detailed outcome analyses in
women could not be performed because of the small number of outcome
events; thus, the prognostic conclusions of these data may not be
generalizable beyond Caucasian men.
Conclusions
In a population-based cohort, cigarette smoking was associated
with two different measures of chronotropic incompetence. Smokers were
more likely to manifest chronotropic impairment than were nonsmokers.
Male smokers who manifested chronotropic incompetence
represented a particularly high-risk subset. Given that
ex-smokers and never smokers had similar chronotropic responses, these
findings suggest that smokers who have chronotropic incompetence should
be aggressively counseled regarding the importance of smoking
cessation.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Reprint requests to Dr Michael S. Lauer, Department of Cardiology, Cleveland Clinic Foundation, Desk F-25, 9500 Euclid Ave, Cleveland, OH 44195.
Received September 30, 1996; revision received February 18, 1997; accepted February 24, 1997.
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