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European Heart Journal Advance Access originally published online on March 14, 2006
European Heart Journal 2006 27(8):954-959; doi:10.1093/eurheartj/ehi832
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Chronotropic response to exercise testing is associated with carotid atherosclerosis in healthy middle-aged men

Sae Young Jae1, Bo Fernhall1,*, Kevin S. Heffernan1, Mira Kang2, Moon-Kyu Lee2, Yoon-Ho Choi2 and Won Hah Park3

1Exercise and Cardiovascular Research Laboratory, Department of Kinesiology and Community Health, College of Applied Life Studies, University of Illinois, Urbana-Champaign, 112 Huff Hall, MC-586, 1206 S. Fourth St Champaign, IL 61820
2Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea
3Center for Health Promotion and Sports Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Received 26 September 2005; revised 9 February 2006; accepted 23 February 2006; online publish-ahead-of-print 14 March 2006.

* Corresponding author. Tel: +1 217 333 2131; fax: +1 217 333 0404. E-mail address: fernhall{at}uiuc.edu

See page 897 for the editorial comment on this article (doi:10.1093/eurheartj/ehi712)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Aims Chronotropic incompetence, an attenuated heart rate (HR) response to exercise, is an independent predictor of cardiovascular mortality, but it is not known whether chronotropic incompetence is related to carotid atherosclerosis. The association between chronotropic incompetence and carotid atherosclerosis in 8567 (age 47.6±8.8 years) healthy men was examined.

Methods and results Chronotropic incompetence was defined as the failure to achieve 85% of the age-predicted maximal HR (APMHR), <80% HR reserve (HRR), and chronotropic response index (CRI). Carotid atherosclerosis was defined, using B-mode ultrasonography, as stenosis >25% and/or intima-media thickness (IMT) of >1.2 mm. In multivariable adjusted logistic regression models, the subjects who achieved less than 85% of APMHR exhibited an odds ratio (OR) of 1.72 [95% confidence intervals (CI): 1.32–2.22] for carotid atherosclerosis. Subjects with <80% of HRR were 1.45 (95% CI: 1.14–1.84) times more likely to have carotid atherosclerosis after multivariate adjustment. Also, the OR of carotid atherosclerosis across quartiles of CRI (highest to lowest) was 1.51 (95% CI: 1.10–2.09) after multivariate adjustment.

Conclusion These results suggest that the chronotropic response to exercise is associated with carotid atherosclerosis, independent of the established risk factors in healthy men, which could contribute to high incidence of cardiovascular diseases in subjects with chronotropic incompetence.

Key Words: Chronotropic incompetence • Carotid • Atherosclerosis • Exercise testing • Heart rate


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 References
 
Chronotropic incompetence, defined as an attenuated heart rate (HR) response to exercise, has been shown to be an independent predictor of coronary artery disease and cardiovascular mortality in healthy subjects.1,2 Although chronotropic incompetence may be associated with autonomic dysfunction,3–5 such as blunted sympathetic nervous activity and parasympathetic withdrawal during exercise, the underlying mechanisms of increased cardiovascular morbidity are not fully understood.

Recently, Fukuma et al.6 indicated that the chronotropic response to exercise is related to decreased baroreceptor sensitivity, and patients with carotid atherosclerosis exhibit decreased HR variability and baroreflex sensitivity.7–9 Furthermore, patients with carotid stenosis have an attenuated HR response to postural change,10 indicative of attenuated baroreceptor sensitivity. Therefore, it is possible that chronotropic response to exercise is related to carotid atherosclerosis. However, this has not yet been investigated.

Carotid atherosclerosis is a marker of cardiovascular disease burden and is also associated with coronary artery disease, stroke, and cardiovascular mortality.11,12 Considering that coronary artery disease is strongly related to carotid atherosclerosis,13,14 an association between chronotropic incompetence and carotid atherosclerosis may be a considerable clinical consequence.

Therefore, our aim is to examine the hypothesis that chronotropic incompetence during exercise stress testing would be associated with carotid atherosclerosis independent of other cardiovascular risk factors.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 References
 
Subjects
We used the data from the Samsung Medical Center in Seoul, Korea between January 2002 and March 2004 for routine medical examinations. These examinations, used for disease prevention/early detection purposes, consisted of: a general physical examination, anthropometric measurements, BP, electrocardiography, blood analysis, carotid or abdominal ultrasound, and an exercise stress test with concurrent metabolic gas analysis. All tests were completed in one visit. From a total sample of 14 232 males, 8567 healthy males (mean age 47.6±8.8 years), who had undergone exercise stress testing without angina symptoms and/or abnormal ECG changes and carotid ultrasound examination, were included in the subsequent analysis. Exclusion criteria included patients with a diagnosis of hypertension, those taking antihypertensive medications (n=1329) or having cardiovascular disease, coronary heart disease (n=57), stroke (n=32), or diabetes. Diabetes was defined as a fasting glucose >126 mg/dL (n=392), or self-reported physician-diagnosed diabetes, or self-reported use of an oral hypoglycaemic agent (n=1174). Also, subjects with a resting BP≥140/90 mmHg (n=514) at the time of the visit, ST depression changes or severe arrhythmias (n=712), and exercise-induced hypotension (n=144) were excluded from data analysis. Informed consent was obtained from all subjects before health screening and the study was approved by the medical center institutional review board.

CVD risk factors
Blood samples were collected following a 12-h overnight fast and analysed by the hospital clinical laboratory approved annually by the College of American Pathologists. Total cholesterol (TC), triglycerides (TG), and high density lipoprotein cholesterol (HDL-C) were analysed enzymatically using a Hitachi 747 (Japan) analyser. Low density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula. The white blood cell count (WBC) was determined using a quantitative automated haematology analyser (Sysmex, Japan). Fibrinogen was measured with the Clauss method using a CA-500 analyser (Sysmex). Fasting glucose levels were determined using the glucose oxidase method (Hitachi-747, Japan) and glycosylated haemoglobin (HbA1c) with an automated ion-exchange chromatographic method. Inter- and intra-assay coefficients of variation were less than 5% for all blood variables.

Assessment of the chronotropic response and exercise stress testing
Weight and body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). Resting HR was measured in the supine position using an electrocardiogram (Hewlett-Packard ECG M 1700A, WI) following at least 5 min of quiet rest. Subjects performed treadmill exercise testing using the Bruce protocol. Expired gases were collected breath-by-breath using a one-way valve and analysed using a metabolic cart (Jaeger Oxycon Delta, Germany). Exercise HR and BP were measured during the last minute of each 3 min stage using 12-lead ECGs (Quinton Q-4500, Bothell, WA) and an automatic BP monitor designed for exercise testing (STBP-680 Colin Corp., Komaki, Japan), respectively. The maximal HR was defined as the highest value achieved during the test. Exercise tests were stopped if one of the following criteria was present: a rating of perceived exertion >17, if the subject achieved >90% of age-predicted maximal HR (APMHR), or if the subject was too fatigued to safely continue walking on the treadmill, >250 mmHg of SBP, or typical chest discomfort, severe arrhythmias, and more than 1 mm of horizontal or downsloping ST segment depression. If subjects had ST depression more than 1 mm, or exercise-induced angina/arrhythmias, they were not included in data analysis.

Chronotropic incompetence was defined by the HR response to a treadmill exercise test using the following three criteria: (i) failure to achieve 85% of the APMHR,1 (ii) less than 80% HR reserve (HRR) achieved,15 and (iii) chronotropic response index (CRI)16 using metabolic equivalents of oxygen uptake.

The percent of achieved APMHR was derived as maximal HR/APMHR (220–age)x100, which has been the traditional definition of chronotropic incompetence.1 However, this method may be confounded by age, resting HR, and/or maximal exercise capacity.1 Therefore, we also assessed the percentage of achieved HRR and CRI. The percent of achieved HRR was calculated as (maximal HR–rest HR)/(APMHRrest–HR)x100. The CRI was calculated as the ratio of the percentage of HRR to the percentage of metabolic reserve used at Stage 2 (4 km/h and 12% grade) of Bruce treadmill protocol as previously described.1,16 All subjects successfully completed stage 2 of the Bruce protocol, and therefore, we calculated CRI from this stage. The following formulas were used: %metabolic reservestage2=(METsstage2–METsrest)/(METspeak–METsrest)x100, where METs indicates the metabolic equivalents of oxygen uptake, which was directly measured by gas analysis, and %HRRstage2=(HRstage2–HRrest)/(APMHR–HRrest)x 100. CRI=%HRRstage2/%metabolic reservestage2.

Carotid atherosclerosis
Carotid artery ultrasound imaging was performed using a high-resolution B-mode ultrasound system (Sonoline Antares, Siemens Medical System, Germany) with a 5–13 MHz linear array transducer. Both the right and left common carotid artery, the carotid bifurcation, and the internal carotid artery were measured, using a standard protocol, by an experienced technician who was unaware of the subject's clinical information. With the subject in a supine position, the carotid arteries were imaged in transverse and longitudinal planes in each segment. The IMT was defined as the distance between the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface of the far wall of carotid artery. All measurements were made at end diastole. The IMT of the common carotid artery was determined from an average of five measurements of a 10 mm segment (separated by 2 mm intervals), obtained 2 cm proximal to the carotid bifurcation. The IMT of internal carotid artery was measured in the proximal 1 cm of the internal carotid artery. The overall maximal IMT was defined as the mean of the maximal IMT of both the common carotid artery and internal carotid artery. An average IMT of >1.2 mm of the carotid arteries was considered indicative of carotid atherosclerosis.17 The stenosis of carotid arteries were defined by the degree of Doppler derived peak systolic velocity (PSV) of the internal carotid artery and categorized as: no stenosis (0–24%, ≤124 cm/s of PSV), mild stenosis (25–49%, >125–149 cm/s of PSV), moderate stenosis (50–70%, >150–174 cm/s of PSV), and severe stenosis (71–99%, >175 cm/s of PSV). Carotid atherosclerosis18 was defined as stenosis >25% and/or IMT >1.2 mm of the carotid arteries. The intra-observer coefficient of variation in our laboratory was 2.3%.

Statistical analysis
Data are expressed as mean±SD for continuous variables, and counts and proportions for categorical variables. Subjects were divided into two groups: those with carotid atherosclerosis and those without carotid atherosclerosis. Two group comparisons were performed using independent t-tests for continuous variables and the {chi}2 test for categorical variables. Pearson's correlations were used to confirm the relationship between chronotropic indexes and age, resting HR, and maximal exercise capacity.

The associations of chronotropic incompetence variables with carotid atherosclerosis (yes or no) were analysed using multivariate logistic regression. However, before performing the multivariable analysis, we investigated potential collinearity between sets of lipid variables using Pearson's correlations. Because of the high correlations between lipid values (r ranging from 0.52 to 0.73), we included only the TC/HDL-C ratio in the models. The selection of variables for entrance into the multivariate model was based on the univariate analysis. Following these evaluations, we selected the following sets of non-collinear variables and univariate associations for multivariable models: age, BMI, smoking (yes or no), SBP, TC/HDL-C ratio, glucose, HbA1c, WBC, resting HR, and VO2 peak.

Analyses of odds ratios (ORs) and 95% confidence intervals (CIs) from multivariate logistic regression models were performed using the proportion of APMHR (entered as a continuous variable) and selected risk factors for atherosclerosis. Because of the strong correlations between the proportion of APMHR, HRR, and CRI (r ranging from 0.61 to 0.99), we entered only the APMHR as a chronotropic incompetence variable in this model. Selected risk factors for carotid atherosclerosis entered into the model included: age, smoking (yes or no), SBP, TC/HDL-C ratio, glucose, HbA1c, WBC, resting HR, and VO2 peak.

Multivariate logistic regression modelling was used to calculate OR and 95% CIs for <80% of HRR and <85% of APMHR (entered as a categorical variable) and selected risk factors, comparing subjects with and without carotid atherosclerosis. Cut-off values were based on previous research.15 Selected risk factors for atherosclerosis entered into the model are already described.

To test for associations between carotid atherosclerosis and CRI, subjects were divided according to the quartiles (entered as a categorical variable). We calculated first the prevalence of carotid atherosclerosis in each quartile using a {chi}2 test. We then performed OR and 95% CIs from crude and adjusted logistic regression models for carotid atherosclerosis across the CRI quartiles, using the highest quartile as reference. The fit of logistic regression model was checked by the Hosmer and Lemeshow test for goodness of fit. All tests for statistical significance were two-sided. Statistical significance was set at P<0.05 for all data. Statistical analyses were performed using the SPSS 12.0 (SPSS, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 References
 
Carotid atherosclerosis was present in 469 men (5.5%). Among the total subjects (n=8567), the prevalence of abnormal chronotropic response to treadmill exercise testing, defined by failure to reach 85% of the APMHR, was 16.5% (n=1416) and 22.5% (n=1924) when defined at HRR<80%.

Two group comparisons are shown in Table 1. The group with carotid atherosclerosis showed significant differences for selected risk factors and variables of exercise testing compared with the group without carotid atherosclerosis (P<0.05). Specifically, there were significant group differences in chronotropic incompetence parameters of percentage target HR achieved (P<0.001), HRR (P<0.001), and CRI (P<0.001). However, BMI, DBP, HDL-C, TG, fibrinogen, and resting HR did not differ between groups.


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  		Table 1 Characteristics of subjects according to carotid atherosclerosis
 
Table 2 shows results from the multivariate logistic regression analysis. Because of the strong correlations between the proportion of APMHR and the proportion of HRR (r=0.99, P<0.001) and CRI (r=0.61, P<0.001), we included only the APMHR as a chronotropic incompetence variable in this model. Selected risk factors and APMHR (continuous data) were significantly associated with carotid atherosclerosis (Table 2). A multivariate logistic model showed that <80% of HRR (categorical data), age, smoking, TC/HDL-C ratio, SBP, and VO2 peak were significantly associated with carotid atherosclerosis (Table 3). Also, subjects with <85% of APMHR (categorical) were more likely to have carotid atherosclerosis in a separate model using the same variables (OR: 1.72, 95% CI: 1.32–2.22; P<0.001) (data not shown).


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  		Table 2 Multivariate ORs (95% CI) for carotid atherosclerosis according to the percentage of achieved APMHR and selected risk factors
 

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  		Table 3 Multivariate ORs (95% CI) for carotid atherosclerosis according to the HR reserve (<80%) and selected risk factors
 
The mean CRI in this study is 0.78±0.16, which is different than previous reports,1 and thus we did not use the previously reported cut-off point of 0.8 for abnormal CRI.1 To evaluate the association between the CRI attained in the current study and the carotid atherosclerosis, subjects were divided into quartiles according to CRI. The prevalence of carotid atherosclerosis in each quartile was 7.6, 6.0, 4.9, and 3.9% in quartiles 1–4, respectively (Figure 1).


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  		Figure 1 Prevalence of carotid atherosclerosis by quartiles of CRI (P<0.001).

 
Table 4 shows multivariable adjusted logistic regression analysis for CRI quartiles. Subjects in the lowest quartile of CRI were more likely to have carotid atherosclerosis than in the highest quartile in crude model (OR: 2.05; 95% CI: 1.52–2.77; P<0.001). After adjusting for selected risk factors (age, smoking, BMI, SBP, TC/HDL-C ratio, glucose, HbA1c, WBC, resting HR, and VO2 peak), the ORs were attenuated but remained associated with a significantly elevated odds of carotid atherosclerosis (OR: 1.51; 95% CI: 1.10–2.09; P=0.012) (Table 4).


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  		Table 4 Multi-variables adjusted ORs (95% CI) for carotid atherosclerosis by quartiles of Chronotropic incompetence index
 
The CRI attained in this study was weakly correlated with age (r=–0.12, P<0.001), resting HR (r=0.06, P<0.001), and VO2 peak (r=0.27, P<0.001). The HRR was also weakly correlated with age (r=–0.11, P<0.001), resting HR (r=0.13, P<0.001), and VO2 peak (r=0.28, P<0.001).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 References
 
The important new findings of this study are that apparently healthy individuals with an attenuated HR response to exercise are more likely to have carotid atherosclerosis. This relationship was independent of selected risk factors for atherosclerosis. To the best of our knowledge, this is the first study to report that chronotropic response to exercise in healthy men is associated with an increased risk of carotid atherosclerosis.

Many studies have reported that an abnormal HR response to exercise is associated with a significantly increased risk of cardiovascular mortality after adjusting for age, exercise capacity, cardiovascular risk factors, and ST segment depression.1,2 Recently, Jouven et al.19 reported that impaired ability to increase HR during exercise stress testing is a powerful predictor of the risk of cardiovascular mortality in 5713 asymptomatic subjects. However, the underlying mechanisms are not completely understood.

Our current finding is important suggesting that apparently healthy subjects with chronotropic incompetence during exercise are at higher risk for the presence of early subclinical atherosclerosis per se. This may not be entirely surprising, because several investigations have showed that patients with known coronary atherosclerosis have a blunted HR response to exercise testing.20,21

Chin et al.22 reported that 72% of the patients with chronotropic incompetence had significant coronary heart disease. Patterson et al.23 showed that achieving <85% of APMHR was associated with a high probability of having left main or three-vessel coronary disease. Balady et al.24 recently showed that subjects who achieved <85% of APMHR had 1.70 times increased risk of coronary heart disease compared with subjects who reached 85% of APMHR during exercise testing. Our data extend those findings, showing that chronotropic incompetence is associated with subclinical carotid atherosclerosis in the absence of diagnosed coronary heart disease or elevated cardiovascular risk factors.

Possible mechanisms
Although the mechanism underlying the associations between chronotropic incompetence and an increased risk of carotid atherosclerosis is not known, there are some possible explanations. Smoking was associated with chronotropic incompetence in the Framingham heart study.25 We also found a higher rate of smokers in the group with an HRR achieved <80% than in the group with an HRR of >80% (40% vs. 27%, P<0.001). Furthermore, smoking is a strong independent predictor of carotid atherosclerosis in middle-aged men.26 An attenuated HR response to exercise is also associated with low cardiorespiratory fitness.27 We found a weak association between the CRI and VO2 peak. Low cardiorespiratory fitness28 is an important independent predictor of carotid atherosclerosis in middle-aged men.

Another possible explanation is that autonomic dysfunction, such as blunted sympathetic nervous activity and parasympathetic withdrawal during exercise may contribute to chronotropic incompetence.26,29,30 In support of this concept, decreased baroreceptor sensitivity has been related to the chronotropic response to exercise.6 It has also been suggested that increased IMT or atherosclerotic changes of the carotid artery decrease compliance of the carotid arterial walls, and is thus responsible for the decreased sensitivity of the receptors in these conditions.7,9 Cai et al.31 reported that dysfunction of the arterial baroreflex facilitate the development of atherosclerosis in an experimental study. Furthermore, Akinola et al.10 reported that patients with carotid stenosis showed an attenuated HR response to postural changes. Therefore, it is also possible that the attenuated chronotropic response to exercise is related to altered carotid baroreflex sensitivity secondary to carotid atherosclerosis. However, our study was not designed to investigate mechanisms, thus our results cannot support or refute these possible mechanisms.

Clinical implications
The HR response to exercise is clinically important because of association with autonomic imbalance and clinical outcome. As both exercise and recovery HRs are related to autonomic function, interpretation of the chronotropic response to exercise should be included as a part of routine exercise testing and may indicate that further clinical evaluation is warranted.

The prevalence of abnormal chronotropic response to treadmill exercise testing in the present study was 17% as defined by failure to reach 85% of the APMHR and 23% as defined by HRR <80% in healthy middle-aged men. This prevalence was similar compared with data from previous reports, where the prevalence of chronotropic incompetence was 15–23%.32 The mean CRI of 0.78 in the present study was lower than expected, and lower than previously reported.1 The difference may be related to the manner in which CRI was calculated. Previous studies have used estimated MET levels based on the treadmill speed and grade. This method may lead to an overestimation of exercise capacity.33 However, we used MET levels derived from the direct measures of VO2 by gas analysis in the calculations of CRI. In addition, we excluded individuals with diagnosed cardiovascular disease including those taking antihypertensive drugs and subjects with diabetes, thereby eliminating important sources of bias and confounders for the prevalence of a ‘pure’ chronotropic response to exercise. Furthermore, we also found that the CRI used in the current study was very weakly associated with age (r=–0.12), resting HR (r=0.06), and VO2 peak (r=0.27). Those correlations are very similar to those reported by Lauer et al.1 However, the clinical utility of CRI derived from directly measured VO2 needs to be investigated in future studies.

Limitations
This study has several limitations. We cannot determine the causation because of the cross-sectional nature of our study and we did not follow the subjects to determine if the chronotropic response to exercise in patients without carotid atherosclerosis was indeed predictive of future diagnoses of carotid atherosclerosis. Also, we do not know if the abnormal CRI attained in the current study is related to the risk of cardiovascular mortality and all-cause mortality. As this study only examined men, findings may not be extended to women. Finally, our measurements of carotid atherosclerosis were used as a screening test, using the presence or absence of increased carotid IMT or stenosis, thus carotid atherosclerosis could only be used as a categorical variable, and not as a continuous variable.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
References
 
These results suggest that an attenuated HR response to treadmill exercise testing is associated with carotid atherosclerosis, independent of established risk factors in healthy men, which could contribute to the higher incidence of cardiovascular diseases in subjects with chronotropic incompetence.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 

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