Association of smoking with abnormal exercise heart rate responses and long-term prognosis in a healthy, population-based cohort

Association of Smoking with Abnormal ExerciseHeart Rate Responses and Long-term Prognosis in

a Healthy, Population-Based Cohort

Ravi Srivastava, MD, Eugene H. Blackstone, MD, Michael S. Lauer, MD

BACKGROUND: Cigarette smoking is associated with chro-notropic incompetence, defined as an attenuated heart rate re-sponse to exercise. The long-term prognostic implications ofthis association have not been well explored.SUBJECTS AND METHODS: Adults enrolled in the Lipid Re-search Clinics’ Prevalence Study who had no history of cardio-vascular disease and who were not taking beta-blockers wereobserved for 12 years. Chronotropic incompetence was assessedas the failure to achieve 90% of an age-predicted target heartrate during an exercise test or as a low chronotropic index, ameasure of exercise heart rate response adjusted for age, restingheart rate, and physical fitness.RESULTS: Of the 5,354 eligible participants (mean [6 SD] ageof 44 6 10 years; 61% male), 1,931 (36%) smoked cigarettes.Smokers were more likely to have a low chronotropic index(26% versus 16%, odds ratio 5 1.8, 95% confidence interval

[CI] 1.6 to 2.1) and fail to achieve an age-predicted target heartrate (32% versus 22%, odds ratio 5 1.7, 95% CI 1.5 to 2.0).Adjustment for standard cardiac risk factors and physical fitnessdid not affect these associations. During follow-up, there were327 deaths. Among subjects without chronotropic incompe-tence, the relative risk of mortality associated with smoking wasmoderately increased (hazard ratio 5 1.8, 95% CI 1.3 to 2.3);among smokers with chronotropic incompetence, the relativerisk of mortality was markedly increased (hazard ratio 5 2.7,95% CI 2.0 to 3.7, P for interaction 5 0.02).CONCLUSIONS: In this large, middle-aged population-basedcohort, smoking was associated with chronotropic incompe-tence, which in turn identified smokers with a particularly highmortality rate. Am J Med. 2000;109:20 –26. q2000 by ExcerptaMedica, Inc.

Chronotropic incompetence, or an attenuatedheart rate response to exercise, increases the riskof all-cause mortality and coronary heart disease,

even after adjusting for age, physical fitness, resting heartrate, standard cardiovascular risk factors, and ST-seg-ment changes with exercise (1–3). Previous reports havedemonstrated that cigarette smoking is associated withchronotropic incompetence among otherwise healthyadults and have suggested that this association may haveprognostic significance (4,5). However, the long-termprognostic implications of this association, particularlywith regard to all-cause mortality, have not been wellstudied.

The purposes of this study were to assess the associa-tion between cigarette smoking and chronotropic incom-petence, and to determine the long-term prognostic sig-nificance of this association in a population-based cohortprimarily comprising middle-aged men and women. We

studied the cohort of subjects enrolled in the Lipid Re-search Clinics Prevalence Study, which was assembledand observed during the 1970s and 1980s. All-cause mor-tality was analyzed as an objective, unbiased outcome(6,7).

MATERIAL AND METHODS

Population SampleThe Lipid Research Clinics’ Prevalence Study was startedin 1972 as a population-based epidemiological investiga-tion of hyperlipidemia (8).

Between 1972 and 1976, a preliminary screening of17,400 men and 16,400 women was performed at 10 par-ticipating centers in the U.S. and Canada. Fasting plasmacholesterol and triglyceride levels were measured duringthis visit. Subjects were invited for a second visit based oneither a random sampling of 15% of the screening popu-lation or if lipid abnormalities were present (8). A total of8200 adult men and women were screened at Visit 2,about 85% of those invited.

As part of their second visit (performed between 1972and 1976), participants underwent a detailed evaluation,which included exercise testing according to the modifiedBruce protocol (9,10), and various blood tests. All sub-jects gave informed consent before the examination.

To be eligible for the current study, subjects had toreach stage 2 of the modified Bruce protocol; exclusioncriteria included the use of beta-blockers or digitalis, a

From the Departments of Medicine (RS), Cardiothoracic Surgery(EHB), Epidemiology and Biostatistics (EHB), and Cardiology (MSL),Cleveland Clinic Foundation, Cleveland, Ohio.

Data supplied by the National Heart, Lung, and Blood Institute. Theviews expressed in this paper are those of the authors and do not nec-essarily reflect the views of the Institute. Dr. Lauer is the recipient of anEstablished Investigator Award of the American Heart Association.

Requests for reprints should be addressed to Michael S. Lauer, MD,Director of Clinical Research and Exercise Laboratory, Department ofCardiology, Desk F25, Cleveland Clinic Foundation, 9500 Euclid Ave-nue, Cleveland, Ohio 44195.

Manuscript submitted October 19, 1999, and accepted in revisedform March 30, 2000.

20 q2000 by Excerpta Medica, Inc. 0002-9343/00/$–see front matterAll rights reserved. PII S0002-9343(00)00441-1

history of atrial fibrillation or flutter, any bundle-branchblock or other baseline ST abnormalities that would pre-clude interpretation of ST-segment changes with exer-cise, pregnancy, any acute illness, congenital heart dis-ease, angina as assessed by the Rose questionnaire (11),stroke, coronary heart disease, and valvular heart disease.

Clinical DataSubjects were questioned in detail about current andprior cigarette smoking. Information on weekly alcoholconsumption, education, medications, and dietary intake(24-hour recall) was also obtained. Baseline level of phys-ical activity was assessed by asking “Do you exercise orlabor at least three times a week?” Height and weight weremeasured; body mass index was calculated by dividingthe weight in kilograms by the square of the height inmeters. Blood pressure at rest was measured after 5 min-utes in a sitting position; the mean value of two measure-ments was recorded.

Exercise TestingAn exercise treadmill test was administered at visit 2 to alleligible participants, according to a modified Bruce pro-tocol (12). The electrocardiogram was monitored contin-uously, while heart rate and blood pressure were mea-sured during each stage. The test was stopped when aprecalculated target heart rate of 90% of the subject’s age-predicted maximal heart rate was attained and main-tained for 1 minute if the subject maintained it until theend of the ongoing exercise stage, or if the subject’s heartrate exceeded the target heart rate by 8 beats per minute,whichever occurred first. The test was terminated beforethe attainment of the target heart rate if the participantwas unable to continue because of chest pain, fatigue,dyspnea, or leg discomfort, or because of abnormalities inthe electrocardiogram (significant ST-segment change,major arrhythmia, or conduction defects), a decrease insystolic blood pressure, technical difficulties, or nonco-operation by the participant. The ST-segment responsewas considered abnormal if there was at least 1 mm ofhorizontal or downsloping ST-segment depression 80msec after the J-point. Exercise capacity in metabolicequivalents (or METs, where 1 MET 5 3.5 mL/kg perminute of oxygen consumption) was estimated usingpreviously published tables (9).

Assessment of Chronotropic ResponseChronotropic incompetence has been defined as the fail-ure to achieve an age-predicted target heart rate (1). Thisdefinition may be affected, however, by age, physical fit-ness, and resting heart rate. Thus, chronotropic responsewas also assessed as the chronotropic index, defined as theratio of the percentage of heart rate reserve used at stage 2of exercise to the percentage of metabolic reserve used(1,4,13). For any given stage of exercise, the percent met-abolic reserve used is defined as [(METSStage 2

METSRest) 4 (METSPeak 2 METSRest)] 3 100. In an anal-ogous fashion, the percent heart rate reserve used is de-fined as [(Heart RateStage 2 Heart RateRest) 4 (220 2Age 2 Heart RateRest)] 3 100. In a group of healthy,nonhospitalized adults undergoing symptom-limited ex-ercise, the chronotropic index is approximately 1 (13).The chronotropic index is largely independent of physicalfitness, age, and resting heart rate, as well as most cardio-vascular risk factors (1). In a previous report of patientsundergoing symptom-limited exercise, we defined achronotropic index value of 0.8 or less as being abnormal(2). Because the exercise protocol used in the currentstudy was not truly symptom limited, we explored differ-ent potential cutoff values between the 10th and 90th per-centiles to identify one that maximized the log-rank chi-square value for prediction of mortality (14). Thus, wedefined chronotropic incompetence as a chronotropicindex (at stage 2 of exercise) of 0.87 or less, referred to asa low chronotropic index.

Follow-upIn 1977, the Lipid Research Clinics’ Mortality Follow-upStudy of all participants who were examined at visit 2 andwho were 30 years of age and older was begun (8). Sub-jects were observed for mortality and cause of death foran average of 12 years; follow-up for vital status was 100%complete.

Statistical AnalysesWe determined the associations between current smok-ing and failure to achieve target heart rate and low chro-notropic index. Stratified analyses were performed forprespecified subgroups based on age, sex, body mass in-dex, use of antihypertensive medications, and physicalactivity. Adjusted odds ratios were calculated using theCochran-Mantel-Haenszel method. Logistic regressionanalyses (15) were used to adjust for age, sex, race, bodymass index, blood pressure, use of antihypertensive med-ications, whether or not subjects exercised at least 3 timesper week, diabetes, serum low-density lipoprotein (LDL)and high-density lipoprotein (HDL) cholesterol levels,serum triglyceride levels, whether invitation to visit 2 wasbased on random sampling or not, ST-segment changeswith exercise, exercise capacity in METs (considered as acontinuous variable), education (defined as at least somecollege), occupation (blue collar or not), and weekly al-cohol consumption. Potential two-way interactions werealso examined.

We estimated the associations between smoking andmortality, stratified for the presence or absence of chro-notropic incompetence, using the Kaplan-Meier productlimit method (16), the log-rank chi-square test, and Coxproportional hazards models (17) that adjusted for thesame set of potential confounders listed above; the pro-portional hazards assumption was confirmed. Particularattention was paid to the interaction of current smoking,

Chronotropic Incompetence and Prognosis/Srivastava et al

July 2000 THE AMERICAN JOURNAL OF MEDICINEt Volume 109 21

chronotropic incompetence, and mortality. All analyseswere performed using Version 6.12 of the SAS statisticalpackage (SAS, Inc, Cary, North Carolina).

RESULTS

Of the 3,266 men and 2,088 women who were eligible foranalyses, 1,931 (36%) were current smokers. Amongsmokers, 280 (15%) smoked ,10 cigarettes per day, 336(17%) smoked 10 –20 cigarettes per day, and 1,315 (68%)smoked .20 cigarettes per day. Smokers were younger,drank more alcohol, and exercised less often (Table 1).Smokers had a lower chronotropic index (Table 2); thiswas primarily explained by a lower proportion of heartrate reserve used. Exercise capacity was similar to that ofnonsmokers, whereas the rate of ischemic ST-segmentchanges was lower in smokers.

Smoking and Chronotropic IncompetenceFailure to achieve target heart rate was observed in 1,373subjects (26%); a chronotropic index of ,0.87 occurredin 1,055 subjects (20%). Current smokers were morelikely to have chronotropic incompetence than were nev-er-smokers or ex-smokers (Figure 1). Because the majordifferences were noted between current smokers and cur-rent nonsmokers (combining never- and ex-smokers), allsubsequent comparisons are between current smokersand current nonsmokers.

A low chronotropic index occurred in 26% of smokerscompared with 16% of nonsmokers (odds ratio [OR] 51.8, 95% confidence interval [CI] 1.6 –2.1, P ,0.001).Failure to achieve 90% of an age-predicted heart rate oc-curred in 32% of smokers compared with 22% of non-smokers (OR 5 1.7, 95% CI 1.5–2.0, P ,0.001). The as-sociations between smoking and these measures of chro-notropic incompetence persisted after stratifying by age,

Table 1. Characteristics by Smoking Status at Baseline

CharacteristicNever Smokers

(n 5 1,867)Ex-Smokers(n 5 1,556)

Current Smokers(n 5 1,931)

Number (Percent) or Mean 6 SD

Age (years) 45 6 11 46 6 11 43 6 9Women 987 (53) 390 (25) 709 (37)Body mass index (kg/m2) 26 6 4 26 6 4 26 6 4Systolic blood pressure (mm Hg) 126 6 18 129 6 18 124 6 16Diastolic blood pressure (mm Hg) 84 6 11 85 6 11 83 6 11Resting heart rate (per minute) 84 6 11 85 6 11 82 6 13Low-density lipoprotein cholesterol (mg/dL) 143 6 42 144 6 40 147 6 41High-density lipoprotein cholesterol (mg/dL) 53 6 15 51 6 16 48 6 15Antihypertensive medications 27 (7) 104 (7) 71 (4)Diabetes 14 (1) 13 (1) 18 (1)Alcohol use (g per week) 7 6 12 14 6 18 16 6 20Exercise 3 times per week 368 (20) 361 (23) 332 (17)

Table 2. Exercise Characteristics by Smoking Status at Baseline

CharacteristicNever

Smokers Ex-SmokersCurrentSmokers

Number (Percent) or Mean 6 SD

Chronotropic index 1.06 6 0.21 1.06 6 0.22 1.00 6 0.23Heart rate at stage 2 (per minute) 142 6 19 138 6 18 138 6 18Increase in heart rate to stage 2 (per minute) 61 6 16 60 6 16 56 6 16Proportion of heart rate reserve used at stage 2 0.66 6 0.20 0.64 6 0.20 0.60 6 0.18Proportion metabolic reserve used at stage 2 0.63 6 0.18 0.61 6 0.17 0.61 6 0.17Peak heart rate (per minute) 162 6 15 161 6 15 160 6 16Peak systolic blood pressure (mm Hg) 168 6 28 172 6 29 169 6 27Exercise workload (METs) 9.9 6 2.4 10.1 6 2.4 10.3 6 2.4Ischemic ST-segment 75 (4) 89 (5) 46 (2)

MET 5 metabolic equivalent.


22 July 2000 THE AMERICAN JOURNAL OF MEDICINEt Volume 109

sex, body mass index, use of antihypertensive medica-tions, and physical activity (Tables 3 and 4). For failure toreach target heart rate, there was a weak interaction withthe frequency of physical activity (Table 3). After multi-variate adjustment, smoking remained associated with

both a low chronotropic index (OR 5 1.9, 95% CI 1.7–2.2, P ,0.0001) and failure to achieve a target heart rate(OR 5 2.5, 95% CI 2.1–2.8, P ,0.0001).

When a low chronotropic index was defined as a valueof 0.80 or less, smoking was strongly associated with a low

Figure 1. Association of smoking status with impaired chronotropic response. The numbers under the bars represent the number ofsubjects in each subgroup.

Table 3. Effects of Smoking on Failure to Achieve for Target Heart Rate

Group Smokers NonsmokersOdds Ratio (95%

Confidence Interval)* P Value†

Number Who Failed to Achieve TargetHeart Rate

Number in Group (Percent)

All 627/1,931 (32) 746/3,423 (22) 1.7 (1.5–2.0) —Age (year)

$60 69/92 (75) 212/375 (57) 2.3 (1.4–3.9) 0.67,60 558/1,839 (30) 534/3,048 (18) 2.1 (1.8–2.4)

SexMale 333/1,222 (27) 368/2,046 (18) 1.7 (1.4–2.0) 0.48Female 294/709 (41) 378/1,377 (27) 1.9 (1.6–2.3)

Body Mass Index (kg/m2)$27 209/645 (32) 283/1,205 (23) 1.6 (1.3–1.9) 0.24,27 418/1,286 (33) 463/2,218 (21) 1.8 (1.6–2.1)

AntihypertensivemedicationsYes 39/71 (55) 94/231 (41) 1.8 (1.0–3.0) 0.96No 588/1,860 (32) 652/3,192 (20) 1.8 (1.6–2.1)

Exercise 3 times per weekYes 53/332 (16) 100/729 (14) 1.2 (0.8–1.7) 0.04No 574/1,599 (36) 646/2,694 (24) 1.8 (1.6–2.0)

* For the association between smoking and failure to achieve target heart rate.† For test of interaction comparing effects of smoking within subgroups.



chronotropic index (18% versus 11%, OR 5 1.9, 95% CI1.6 –2.2, P ,0.0001). This association persisted in a mul-tivariate analysis (OR 5 2.0, 95% CI 1.7–2.4, P ,0.0001).

Smoking, Chronotropic Incompetence, andMortalityDuring 12 years of follow-up, there were 327 deaths (231men and 96 women). When subjects were classified by

smoking status and chronotropic response, those whoboth smoked and had a low chronotropic index hadmarkedly greater all-cause mortality (Figure 2). In age-and sex-adjusted analyses, mortality was associated withsmoking (hazard ratio 5 2.0, 95% CI 1.6 –2.5, P,0.0001), a low chronotropic index (hazard ratio 5 1.5,95% CI 1.2–1.9, P 5 0.001), and failure to reach targetheart rate (hazard ratio 5 1.7, 95% CI 1.3–2.1, P

Figure 2. Kaplan-Meier plot of overall survival by smoking status and chronotropic index.

Table 4. Effects of Smoking on Low Chronotropic Index (#0.87)

Group Smokers NonsmokersOdds Ratio (95%

Confidence Interval)* P Value†

Number with Low Chronotropic Index

Number in Group (Percent)

All 503/1,931 (26) 552/3,423 (16) 1.8 (1.6–2.1) —Age (year)

$60 31/92 (34) 76/375 (20) 2.0 (1.2–3.3) 0.79,60 472/1,839 (26) 476/3,048 (16) 1.9 (1.6–2.2)

SexMale 319/1,222 (26) 358/2,046 (18) 1.7 (1.4–2.0) 0.09Female 184/709 (26) 194/1,377 (14) 2.1 (1.7–2.7)

Body Mass Index (kg/m2)$27 162/645 (25) 174/1,205 (14) 2.0 (1.6–2.5) 0.41,27 341/1,286 (27) 378/2,218 (17) 1.8 (1.5–2.1)

Antihypertensive medicationsYes 22/71 (31) 49/231 (21) 1.7 (0.9–3.0) 0.72No 481/1,860 (26) 503/3,192 (16) 1.9 (1.6–2.2)

Exercise 3 times per weekYes 106/332 (32) 160/729 (22) 1.7 (1.3–2.2) 0.37No 397/1,599 (25) 392/2,694 (15) 1.9 (1.7–2.3)

* For the association between smoking and low chronotropic index.† For test of interaction comparing effects of smoking within subgroups.



,0.0001). A low chronotropic index was associated withmortality among smokers (hazard ratio 5 1.6, 95% CI1.2–2.3, P 5 0.005) but not among nonsmokers (hazardratio 5 1.1, 95% CI 0.8 –1.6, P 5 0.46, P for interaction 50.004). Similarly, after adjustment for age and sex, failureto reach a target heart rate was associated with mortalityamong smokers (hazard ratio 5 1.9, 95% CI 1.3–2.7, P 50.0008) but not among nonsmokers (hazard ratio 5 1.2,95% CI 1.2–1.7, P 5 0.19, P for interaction 5 0.001).

After multivariate adjustment, smokers with normalchronotropic index had moderately increased mortality(hazard ratio associated with smoking 5 1.8, 95% CI 1.3–2.3, P ,0.0001), whereas smokers with a low chrono-tropic index had a substantially increased mortality (haz-ard ratio 5 2.7, 95% CI 2.0 –3.7, P ,0.0001). The inter-action among smoking, chronotropic incompetence, andall-cause mortality was statistically significant (P 5 0.02).When a cutoff of 0.80 for a low chronotropic index wasused, the relative risk of mortality associated with smok-ers who had chronotropic incompetence (hazard ratio 52.5, 95% CI 1.6 –3.6) was greater than that among smok-ers without chronotropic incompetence (hazard ratio 51.9, 95% CI 1.5–2.5); the interaction term was not statis-tically significant (P 5 0.22).

Similar results were noted when failure to reach targetheart rate was considered. After multivariate adjustment,smokers who reached their target heart rate had a mod-erately increased mortality (hazard ratio associated withsmoking 5 1.6, 95% CI 1.1–2.2, P 5 0.007), whereassmokers who failed to reach their target heart rate had amarkedly increased mortality (hazard ratio 5 2.5, 95% CI2.0 –3.2, P ,0.0001). The interaction between smoking,failure to reach target heart rate, and mortality was statis-tically significant (P 5 0.01).

Of the 327 deaths, 114 (35%) were thought to havebeen due to cardiovascular causes, based on review ofdeath certificates. In all participants, cardiovascular deathwas associated with both a low chronotropic index (age-and sex-adjusted hazard ratio 5 1.5, 95% CI 1.0 –2.2, P 50.07) and failure to reach a target heart rate (hazard ra-tio 5 1.8, 95% CI 1.2–2.6, P 5 0.006). Smokers with anormal chronotropic index were at increased risk of car-diovascular death (hazard ratio 5 2.2, 95% CI 1.4 –3.4,P 5 0.0004) as were smokers with a low chronotropicindex (hazard ratio 5 3.5, 95% CI 2.1–5.8, P ,0.0001, Pfor interaction 5 0.10). Similarly, smokers who reachedtheir target heart rate were at increased risk of cardiovas-cular death (hazard ratio 5 2.0, 95% CI 1.2–3.3, P 50.006), and those who failed to reach their target heartrate had an even greater mortality (hazard ratio 5 3.2,95% CI 2.1– 4.9, P ,0.0001, P for interaction 5 0.10).

DISCUSSION

In this population-based cohort of healthy, primarilymiddle-aged adults, cigarette smoking was strongly and

independently associated with chronotropic incompe-tence, whether assessed by failure to achieve target heartrate or by a low chronotropic index. This association hadprognostic importance, in that the detrimental effects ofsmoking on mortality were significantly greater if chro-notropic incompetence was also present.

Several groups have previously shown that smoking isassociated with a reduced exercise tolerance and an ab-normal chronotropic response (18,19). Gordon and col-leagues (5) previously studied subjects who were screenedfor the Lipid Research Clinics’ Coronary Primary Preven-tion Trial, a different cohort from that reported in thisstudy. They found that smokers were nearly twice as likelyto stop exercising due to fatigue, dyspnea, or leg pain evenafter adjusting for other risk factors. We previously re-ported the association between smoking and chrono-tropic incompetence in the Framingham Heart Study (4).As in the present study, current smoking was stronglyassociated with chronotropic incompetence. Smokerswith chronotropic incompetence had a markedly in-creased risk of death and coronary heart disease events;however, the relatively small number of events precludedrobust multivariable analyses.

The current study confirms and extends our previousfindings. In addition to demonstrating a strong associa-tion between smoking and chronotropic incompetence,we also found that chronotropic incompetence affects theassociation between smoking and mortality in that smok-ing is correlated with particularly high risk when chrono-tropic incompetence is also present.

How cigarette smoking leads to chronotropic incom-petence is not known. Smoking has many adverse cardio-pulmonary effects, including coronary vasoconstriction(20) and myocardial ischemia (21). It is not clear whetherthese can explain the altered heart rate responses insmokers. Another possibility may be related to auto-nomic alterations from chronic nicotine intake. Smokingis related to the down-regulation of beta-adrenergic re-ceptors (22,23). Smokers who quit have improvements inheart rate variability, which improve, further after cessa-tion of a transdermal nicotine patch (24). Smoking raisesresting heart rate and blood pressure (25) and is associ-ated with enhanced local catecholamine release (26).Chronic sympathetic overload related to nicotine intakemay lead to decreased sympathetic reserve, which hasbeen linked to chronotropic incompetence, such asamong patients with chronic heart failure (27). This pat-tern of increased sympathetic tone and decreased para-sympathetic tone has been linked to increased mortality(28), perhaps because of increased vulnerability to ar-rhythmias.

Our study has several limitations. The exercise tests inthe Lipid Research Clinics’ Prevalence Study were sub-maximal, not symptom limited. In addition, the use of anincremental exercise treadmill protocol may lead to the



overestimation of exercise capacity (29). Nonetheless, anassociation between chronotropic incompetence and ad-verse outcomes has been shown in other groups of pa-tients who have undergone submaximal testing (1). Al-though this cohort was population based, it may not havebeen as representative of the general population as theFramingham Heart Study, given that the purpose of thestudy was an investigation of hyperlipidemia. We did notemphasize deaths by presumed cause in great detail dueto the problems associated with cause-specific analyses(7).

In conclusion, we found that in a large, middle-agedpopulation-based cohort, cigarette smoking was stronglyassociated with chronotropic incompetence, which inturn identified a group of smokers who were at increasedrisk of mortality. Although all smokers should be urged toquit, chronotropic incompetence may be a clinically use-ful marker to identify smokers for whom smoking cessa-tion is particularly important.

REFERENCES1. Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. Impaired heart

rate response to graded exercise. Prognostic implications of chro-notropic incompetence in the Framingham Heart Study. Circula-tion. 1996;93:1520 –1526.

2. Lauer MS, Francis GS, Okin PM, et al. Impaired chronotropic re-sponse to exercise stress testing as a predictor of mortality. JAMA.1999;281:524 –529.

3. Ellestad MH. Chronotropic incompetence. The implications ofheart rate response to exercise (compensatory parasympathetic hy-peractivity?). Circulation. 1996;93:1485–1487.

4. Lauer MS, Pashkow FJ, Larson MG, Levy D. Association of cigarettesmoking with chronotropic incompetence and prognosis in theFramingham Heart Study. Circulation. 1997;96:897–903.

5. Gordon DJ, Leon AS, Ekelund LG, et al. Smoking, physical activity,and other predictors of endurance, and heart rate response to exer-cise in asymptomatic hypercholesterolemic men. The Lipid Re-search Clinics Coronary Primary Prevention Trial. Am J Epidemiol.1987;125:587– 600.

6. Gottlieb SS. Dead is dead—artificial definitions are no substitute.Lancet. 1997;349:662– 663.

7. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death inclinical research: time for a reassessment? J Am Coll Cardiol. 1999;34:618 – 620.

8. Ekelund LG, Haskell WL, Johnson JL, et al. Physical fitness as apredictor of cardiovascular mortality in asymptomatic NorthAmerican men. The Lipid Research Clinics Mortality Follow-upStudy. NEJM. 1988;319:1379 –1384.

9. Fletcher GF, Balady G, Froelicher VF, et al. Exercise standards. Astatement for healthcare professionals from the American HeartAssociation Writing Group. Circulation. 1995;91:580 – 615.

10. Doan AE, Peterson DR, Blackmon JR, Bruce RA. Myocardial isch-

emia after maximal exercise in healthy men. One year follow-up ofphysically active and inactive men. Am J Cardiol. 1966;17:9 –19.

11. Haskell WL, Taylor HL, Wood PD, et al. Strenuous physical activ-ity, treadmill exercise test performance and plasma high-densitylipoprotein cholesterol. The Lipid Research Clinics Program Prev-alence Study. Circulation. 1980;62(4 Pt 2):IV53– 61.

12. Sheffield LT, Haskell WL, Heiss G. Safety of exercise testing volun-teer subjects: the Lipid Research Clinics’ Prevalence Study experi-ence. J Cardiac Rehab. 1982;2:395– 400.

13. Wilkoff BL, Miller RE. Exercise testing for chronotropic assess-ment. Cardiol Clin. 1992;10:705–717.

14. LeBlanc M, Crowley J. Relative risk trees for censored survival data.Biometrics. 1992;48:411– 425.

15. Hosmer D, Lemeshow S. Applied Logistic Regression. New York:Wiley; 1989.

16. Kaplan E, Meier P. Nonparametric estimation from incompleteobservations. J Am Stat Soc. 1958;53:457– 481.

17. Cox D. Regression models and life tables. J Roy Stat Soc B. 1972;34:187–220.

18. Sidney S, Sternfeld B, Gidding SS, et al. Cigarette smoking andsubmaximal exercise test duration in a biracial population of youngadults: the CARDIA study. Med Sci Sports Exerc. 1993;25:911–916.

19. Conway TL, Cronan TA. Smoking, exercise, and physical fitness.Prev Med. 1992;21:723–734.

20. Moliterno DJ, Willard JE, Lange RA, et al. Coronary-artery vaso-constriction induced by cocaine, cigarette smoking, or both. NEJM.1994;330:454 – 459.

21. Barry J, Mead K, Nabel EG, et al. Effect of smoking on the activity ofischemic heart disease. JAMA. 1989;261:398 – 402.

22. Laustiola KE, Lassila R, Kaprio J, Koskenvuo M. Decreased beta-adrenergic receptor density and catecholamine response in malecigarette smokers. A study of monozygotic twin pairs discordant forsmoking. Circulation. 1988;78(5 Pt 1):1234 –1240.

23. Laustiola KE, Kotamaki M, Lassila R, et al. Cigarette smoking alterssympathoadrenal regulation by decreasing the density of beta 2-ad-renoceptors. A study of monitored smoking cessation. J CardiovascPharmacol. 1991;17:923–928.

24. Stein PK, Rottman JN, Kleiger RE. Effect of 21 mg transdermalnicotine patches and smoking cessation on heart rate variability.Am J Cardiol. 1996;77:701–705.

25. Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: im-plications for nicotine replacement therapy. J Am Coll Cardiol.1997;29:1422–1431.

26. Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrineand epinephrine release and adrenergic mediation of smoking-as-sociated hemodynamic and metabolic events. NEJM. 1976;295:573–577.

27. Colucci WS, Ribeiro JP, Rocco MB, et al. Impaired chronotropicresponse to exercise in patients with congestive heart failure. Role ofpostsynaptic beta-adrenergic desensitization. Circulation. 1989;80:314 –323.

28. La Rovere MT, Bigger JT, Marcus FI, et al. Baroreflex sensitivity andheart rate variability in prediction of total cardiac mortality aftermyocardial infarction. Lancet. 1998;351:478 – 484.

29. Myers J, Buchanan N, Walsh D, et al. Comparison of the rampversus standard exercise protocols. J Am Coll Cardiol. 1991;17:1334 –1342.



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Association of smoking with abnormal exercise heart rate responses and long-term prognosis in a healthy, population-based cohort