Association of Cigarette Smoking With Chronotropic Incompetence and Prognosis in the Framingham Heart Study
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.
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.
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 β-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.
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
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.
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
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 χ2 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)]×100.
In an analogous fashion, for the percent heart rate reserve (HRR) used is: %HRR used=[(HRstage − HRrest)/(220 − age − HRrest)]×100.
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.
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%), β-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%), β-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.
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.
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.
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⇓).
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.
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⇓).
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).
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.
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 β-adrenergic receptors. Further studies will be needed to determine whether this or other mechanisms can account for the association between smoking and impaired chronotropy.
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.
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.
Selected Abbreviations and Acronyms
|FEV1||=||first-second forced expiratory volume|
|FVC||=||forced vital capacity|
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.
- Copyright © 1997 by American Heart Association
Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. Impaired heart rate response to graded exercise: prognostic implications of chronotropic incompetence in the Framingham Heart Study. Circulation. 1996;93:1520-1526.
Ellstad MH. Chronotropic incompetence: the implications of heart rate response to exercise (compensatory parasympathetic hyperactivity?) Circulation. 1996;93:1485-1487.
Gordon DJ, Leon AS, Ekelund LG, Sopko G, Probstfield JL, Rubenstein C, Sheffield LT. Smoking, physical activity, and other predictors of endurance and heart rate response to exercise in asymptomatic hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial. Am J Epidemiol. 1987;125:587-600.
Dawber TR, Meadors GR, Moore FE. Epidemiologic approaches to heart disease: the Framingham Heart Study. Am J Public Health. 1951;41:279-286.
Dawber TR, Kannel WB, Lyell LP. An approach to longitudinal studies in a community: the Framingham Study. Ann N Y Acad Sci. 1963;107:539-556.
Kannel WB, Feinlieb M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am J Epidemiol. 1979;110:281-290.
Doan AE, Peterson DR, Blackmon JR, Bruce RA. Myocardial ischemia after maximal exercise in healthy men. Am Heart J. 1965;69:11-25.
Kannel WB, Sorlie P. Some health benefits of physical activity: the Framingham Study. Arch Intern Med. 1979;139:857-861.
The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993;153:154-183.
Shurtleff D. Some characteristics related to the incidence of cardiovascular disease and death: the Framingham Study 18-year followup. In: Kannel WB, Gordon T, eds. The Framingham Study: An Epidemiologic Investigation of Cardiovascular Disease. Washington, DC: Government Printing Office; 1974, DHEW publication No. (NIH) 74-599.
Sheffield LT. Graded exercise tests for ischemic heart disease. In: Exercise Testing and Training of Apparently Healthy Individuals: A Handbook for Physicians. Dallas, Tex: American Heart Association; 1975:35-38.
American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 3rd ed. Philadephia, Pa: Lea & Febiger; 1986:26, Fig 2⇑-4.
Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment. Cardiol Clin. 1992;10:705-717.
Hosmer DW, Lemeshow S. Applied Logistic Regression. New York, NY: Wiley; 1989:25-175.
Cox DR. Regression models and life tables (with discussion). J R Stat Soc B. 1972;34:187-220.
SAS Institute Inc. SAS/STAT User’s Guide, Version 6, 4th ed. Cary, NC: SAS Institute Inc; 1989.
Sidney S, Sternfeld B, Gidding SS, Jacobs DR, Bild DE, Oberman A, Haskell WL, Crow RS, Gardin JM. Cigarette smoking and submaximal exercise test duration in a biracial population of young adults: the CARDIA study. Med Sci Sports Exerc. 1993;25:911-916.
McHenry PL, Faris JV, Jordan JW, Morris SN. Comparative study of cardiovascular function and ventricular premature complexes in smokers and nonsmokers during maximal treadmill exercise. Am J Cardiol. 1977;39:493-498.
Conway TL, Cronan TA. Smoking, exercise, and physical fitness. Prev Med. 1992;21:723-734.
Moliterno DJ, Willard JE, Lange RA, Negus BH, Boehrer JD, Glamann B, Landau C, Rossen JD, Winniford MD, Hillis LD. Coronary artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med. 1994;330:454-459.
Kiowski W, Linder L, Stoschitzky K, Pfisterer M, Burckhardt D, Burkart F, Buhler FR. Diminished vascular response to inhibition of endothelium-derived nitric oxide and enhance vasoconstriction to exogenously administered endothelin-1 in clinically healthy smokers. Circulation. 1994;90:27-34.
Barry J, Mead K, Nabel EG, Rocco MB, Campbell SC, Fenton T, Mudge GH, Selwyn AP. Effect of smoking on the activity of ischemic heart disease. JAMA. 1989;261:398-402.
Kool MJF, Hoeks APG, Struijker Boudier HAJ, Reneman RS, VanBortel LMAB. Short- and long-term effects of smoking on arterial wall properties in habitual smokers. J Am Coll Cardiol. 1993;22:1881-1886.
Higgins MW, Enright PL, Kronmal RA, Schenker MB, Anton-Culver H, Lyles M. Smoking and lung function in elderly men and women: the Cardiovascular Health Study. JAMA. 1993;269:2741-2748.
Stein PK, Rottman JN, Kleiger RE. Effect of 21 mg transdermal nicotine patches and smoking cessation on heart rate variability. Am J Cardiol. 1996;77:701-705.
Quillen JE, Rossen JD, Oskarsson HJ, Minor RL, Lopez AG, Winniford MD. Acute effect of cigarette smoking of the coronary circulation: constriction of epicardial and resistance vessels. J Am Coll Cardiol. 1993;22:642-647.
Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. N Engl J Med. 1976;295:573-577.
Francis GS, Goldsmith SR, Ziesche S, Nakajima H, Cohn JN. Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure. J Am Coll Cardiol. 1985;5:832-839.
Myers J, Buchanan N, Walsh D, Kraemer M, McAuley P, Hamilton Wessler M, Froelicher VF. Comparison of the ramp versus standard exercise protocols. J Am Coll Cardiol. 1991;17:1334-1342.