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(Chest. 2004;125:1286-1291.)
© 2004 American College of Chest Physicians

Association of an Abnormal Exercise Heart Rate Recovery With Pulmonary Function Abnormalities*

Niranjan Seshadri, MD; Thomas R. Gildea, MD; Kevin McCarthy, RCPT; Claire Pothier, MS; Mani S. Kavuru, MD, FCCP and Michael S. Lauer, MD

* From the Departments of Cardiology (Drs. Seshadri and Lauer, and Ms. Pothier) and Pulmonary Medicine (Drs. Gildea and Kavuru, and Mr. McCarthy), Cleveland Clinic Foundation, Cleveland, OH.

Correspondence to: Michael S. Lauer, MD, Director of Clinical Research, Department of Cardiology, Desk F25, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: Lauerm{at}ccf.org


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Heart rate recovery (HRR) after exercise correlates with decreased vagal tone and mortality. Patients with COPD may have altered autonomic tone. We sought to determine the association of HRR with spirometry measures of pulmonary function.

Methods: We analyzed 627 patients (mean [± SD] age, 58 ± 12 years; 65% men; mean FEV1, 2.6 ± 0.9 L, 80 ± 20% predicted; patients receiving inhaled ß2 agonist therapy, 10%; patients receiving inhaled anticholinergic therapy, 3%; patients receiving inhaled steroids, 5%; patients receiving oral prednisone, 4%) who had undergone maximal exercise testing and had undergone pulmonary function tests < 1 year apart. Patients with heart failure, pacemakers, and atrial fibrillation were excluded. Abnormal HRR was defined as a fall in heart rate during the first minute after exercise of <= 12 beats/min (<= 18 beats/min with stress echocardiography). Patients were divided into quartiles based on FEV1 percent predicted.

Results: An abnormal HRR was seen in 229 patients (36%). The mean FEV1 values broken into quartiles 1 to 4 were 54 ± 11% predicted, 74 ± 3% predicted, 87 ± 4% predicted, and 106 ± 10% predicted. In smokers and nonsmokers, a worsening FEV1 percent predicted was associated with an abnormal HRR. In a multivariable model accounting for confounding factors including medications and functional capacity, the predictors of an abnormal HRR included FEV1 percent predicted (adjusted odds ratio for 1 SD decrease, 1.32; 95% confidence interval, 1.07 to 1.65; p = 0.0004), impaired functional capacity, male gender, and age.

Conclusions: Abnormalities found on spirometry are associated with abnormal HRR, which may reflect an altered autonomic tone associated with pulmonary dysfunction, either obstructive or restrictive in nature.

Key Words: autonomic nervous system • COPD • heart rate • exercise testing • pulmonary function


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
COPD may be associated with abnormalities in autonomic tone.12345 The presence of subclinical or clinical autonomic dysfunction, as assessed by heart rate variability or baroreceptor insensitivity, is predictive of increased mortality.678 Another important measure of autonomic dysfunction is heart rate recovery (HRR), an easily acquired measure obtained immediately after graded exercise testing that is reflective of parasympathetic tone.9 An attenuated HRR has been shown in multiple cohorts to predict mortality59101112 and cardiovascular events.13 Because of the association of COPD with autonomic imbalance12345 and because it has been suggested that indexes of heart rate variability may be of prognostic value in COPD patients,4 we hypothesized that there should also be an association with obstructive pulmonary flow abnormalities with HRR. To the best of our knowledge, there are no published data on the association of pulmonary function test (PFT) measures of airway function and exercise heart rate dynamics.

We aimed to determine whether abnormalities of pulmonary function, as detected by spirometry, are independently associated with an abnormal HRR following graded treadmill exercise testing.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Population
The study cohort consisted of 627 consecutive patients who underwent graded treadmill exercise testing at the Cleveland Clinic Foundation between 1990 and 1999, and who also underwent pulmonary spirometry within 1 year. Patients with atrial fibrillation, those with a history of congestive heart failure, permanent pacemaker implantation, heart transplantation, or peripheral vascular disease, or those who were receiving digoxin were excluded from the study. All patients gave informed consent prior to undergoing exercise testing and PFTs. The local institutional review board approved the performance of clinical research based on the routine collection of data among patients undergoing stress testing at the Cleveland Clinic Foundation.

Clinical History
As part of their routine clinical evaluation, all patients gave a detailed history and underwent physical examination, which included a thorough review of systems, cardiovascular risk factor profile, past illnesses, medication use, and prior cardiac and noncardiac procedures, by a clinician or an exercise physiologist. This evaluation has been described in detail elsewhere.111415

Exercise Testing, Chronotropic Response, and HRR
All patients underwent maximum symptom-limited exercise treadmill tests using standardized exercise protocols.16 Patients were encouraged to continue exercising until they were limited by symptoms, even if they achieved the desired goal of 85% of the maximum predicted heart rate. A resting ECG was performed and repeated at the end of each stage during exercise, at peak effort, and during the recovery phases. Data on heart rate and BP also were collected during these phases. At the end of the test, exercise capacity in metabolic equivalents (MET [where 1 MET is approximately equal to oxygen consumption of 3.5 mL/kg/min]) was estimated, with patients classified as having average or better, fair, or poor physical fitness for age and gender, according to a previously validated scheme.15

Chronotropic response was assessed by the proportion of heart rate reserve used at peak exercise, a measure of chronotropic response that is independent of age and exercise capacity, and that is independently predictive of mortality.17 This can be expressed mathematically as a chronotropic response index of (peak heart rate – resting heart rate)/(220 – age – resting heart rate).17 A value of <= 80% in the absence of concurrent ß-blocker therapy was defined as chronotropic incompetence, as this has been shown to be a powerful predictor of mortality.17

HRR was defined as the change in heart rate from peak exercise to 1 min later. For patients undergoing an upright cool-down period during the first few minutes of recovery, an abnormal value was defined as a fall in heart rate during the first minute after peak exercise of <= 12 beats/min.11 For example, a patient with a peak heart rate of 160 beats/min would need to have a fall in heart rate to <= 147 beats/min in order to manifest a normal HRR. For patients undergoing exercise echocardiography, an abnormal value was defined as <= 18 beats/min. The justification for these differential cutoff values has been described in detail elsewhere.17

Spirometry
Spirometry reports were performed by trained pulmonary function technicians using pneumotachographs (Jaeger; Wurzburg, Germany) according to the American Thoracic Society guidelines.18 Spirometry results were analyzed using computer-assisted interpretation with reference standards derived from the National Health and Nutrition Examination Study III database.19 Based on the results of spirometry testing, COPD severity was graded into categories of none (FEV1/FVC ratio at the lower limits of normal [LLN] or greater), mild (FEV1/FVC ratio less than the LLN, and FEV1 less than the LLN and >= 70% predicted), moderate (FEV1/FVC less than LLN, and FEV1 between 50% and 70% predicted), and severe (FEV1 <= 50% predicted).

Statistical Analysis
The study cohort was divided into quartiles based on FEV1 percent predicted. Differences in exercise characteristics were analyzed using the Mantel-Haenszel extension {chi}2 tests and Kruskal-Wallis test as appropriate. Prevalence ratios and confidence intervals (CIs) relating the frequency of an abnormal HRR to PFT measures were calculated. Prevalence ratios were calculated from odds ratios (ORs) using the method of Zhang and Yu.20

Multivariable bootstrap-validated logistic regression21 modeling was used to assess the impact of potential confounders on the association of PFT measures and an abnormal HRR. Variables included in the bootstrap model included age, gender, race, smoking status, diabetes, hypertension, body mass index, history (including coronary artery disease, coronary artery bypass surgery, or percutaneous coronary intervention), systolic BP, diastolic BP, history of diabetes, prior myocardial infarction as determined by ECG, left bundle-branch block, lower functional capacity, chronotropic incompetence in the absence of ß-blockade, and medications (including use of lipid-lowering therapy, angiotensin-converting enzyme inhibitors, diuretics, calcium channel blockers, ß-blockers, oral prednisone, inhaled sympathomimetics, inhaled anticholinergics, and inhaled steroids). Two series of bootstrapping resamplings and modeling were performed, one for variable selection and one for parameter estimation.22 Those variables that entered at least 50% of models on the first set of bootstraps were automatically entered into the second set. The purpose of these resamplings was to minimize the effects of overly influential observations and decrease "overoptimism" related to the analysis of only one data set. Potentially important interactions were tested. All analyses were performed using a statistical software package (SAS, version 8.2; SAS Institute; Cary, NC).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline clinical and exercise characteristics according to quartiles of FEV1 percent predicted are shown in Tables 1and 2 . In the entire population sample, the mean (± SD) age was 58 ± 12 years, and 406 (65%) were men, 184 (29%) were current or recent smokers, and 150 (24%) had a history of coronary artery disease. The mean FEV1 values were 2.6 ± 0.9 L and 80 ± 20% predicted. There were 474 patients (76%) with no obstructive lung disease, 51 (8%) with mild COPD, 70 (11%) with moderate COPD, and 32 (5%) with severe COPD. At the time of exercise testing, therapy with ß-blockers was being used regularly by 121 patients (19%), with inhaled ß2-agonists by 61 patients (10%), with inhaled anticholinergics by 18 patients (3%), with oral theophylline by 10 patients (2%), with inhaled steroids by 29 patients (5%), and with oral prednisone by 23 patients (4%). Among the 65 patients in the lowest quartile of FEV1 percent predicted who did not have COPD, all had measures consistent with restrictive lung disease.


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  		Table 1.. Baseline Clinical Characteristics in All Patients*

 

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  		Table 2.. Baseline Exercise Characteristics in All Patients*

 
An abnormal HRR was seen in 229 patients (36%). The mean FEV1 in quartiles 1 to 4 were 54 ± 11% predicted, 74 ± 3% predicted, 87 ± 4% predicted, and 106 ± 10% predicted, respectively. As shown in Table 2, patients with a reduced FEV1 percent predicted had lower HRRs following exercise testing and a higher prevalence of abnormal HRRs. A reduced FEV1 percent predicted also was associated with a lower chronotropic index, lower peak METs in men and women, lower peak heart rates, and worse functional capacity.

The unadjusted and adjusted prevalence ratios for an abnormal HRR by quartiles of PFT measures of lung function are shown in Table 3 . In smokers and nonsmokers, worsening FEV1 percent predicted was associated with an abnormal HRR, as shown in Figure 1 .


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  		Table 3.. Prevalence of Abnormal HRR With Various PFT Measures in Terms of PFT Quartiles*

 


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  		Figure 1.. Association of abnormal HRR with spirometry measurements according to quartiles of FEV1 percent predicted.

 
In multivariable bootstrap-validated logistic regression models accounting for possible confounding factors including medications and functional capacity, predictors of an abnormal HRR included older age, higher resting heart rate, male gender, fair or poor functional capacity for age and gender, 1 SD decrease in FEV1 percent predicted (after logarithmic transformation), and smoking (current or recent) [Table 4 ].


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  		Table 4.. Multivariable Predictors of Abnormal HRR*

 
Because therapy with ß-blockers might have an effect on heart rate dynamics, we performed two supplementary analyses. First, we forced the use of ß-blockade into a logistic model and found no significant association with the presence of an abnormal HRR (adjusted OR, 1.31; 95% CI, 0.78 to 2.20; p = 0.30). Second, we tested an interaction term of FEV1 percent predicted with ß-blocker use for association with an abnormal HRR, and this term was not found to be significant (p = 0.48).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We showed an association of abnormal HRR following maximal symptom-limited exercise testing and spirometry measurements of impaired pulmonary function. This association prevailed even after adjusting for multiple possible confounding factors in a multivariable model.

HRR following exercise testing correlates with vagal tone, and a decrease of HRR in the first minute after peak exercise is associated with increased mortality.11 In patients with COPD, there may be an alteration in autonomic tone. Stewart et al3 suggested that there might be an association between subclinical autonomic dysfunction measured by heart rate responses to Valsalva maneuver, deep breathing, and postural changes, and the presence of arterial hypoxemia in patients with COPD. In another similar study, Stewart et al2 also showed that autonomic dysfunction, as measured by the acetylcholine sweat-spot test, correlated with the severity of hypoxemia. There is evidence of QTc prolongation in patients with hypoxemic COPD, especially in those with other evidence of autonomic dysfunction.1 Patients with COPD also may have decreased heart rate variability.45 In one study, 31 patients with COPD with a mean FEV1 of 52% had depressed heart rate variability compared to control subjects.5

It is noteworthy that 65 of the persons in the lowest quartile for FEV1 percent predicted (42%) had restrictive measurements. This observation may be seen as extending the hypothesis relating lung disease to autonomic dysfunction. That is, lung disease of obstructive, restrictive, and mixed types may be associated with autonomic imbalance. To our knowledge, there are no data linking autonomic dysfunction to restrictive lung disease. Thus, further research is needed to determine how the type of pulmonary dysfunction correlates with autonomic abnormalities.

Our study has limitations. We did not obtain arterial blood gas data on our patients. The exercise tests and spirometry measurements were not performed simultaneously. We did not have detailed, quantified smoking histories on our patients. However, detailed self-reported smoking histories are not always reliable, as demonstrated by studies232425 showing a discrepancy between the self-reported cessation of smoking and objective measures such as measurements of thiocyanate and cotinine levels. Furthermore, in patients with lifetime tobacco exposure of > 5 pack-years, the reliability of retrospectively estimated pack-years of smoking is poor.26

Previous work4 has shown that in stable patients with COPD, measures of heart rate variability may be useful clinically for the assessment of prognosis. Heart rate variability measures require prolonged heart rate recordings and specialized software, whereas HRR measures obtained right after exercise are simple to obtain, are understood intuitively, and are inexpensive. Combining the findings of the present study with the known association between HRR and vagal tone,9 it is likely that HRR may emerge as a useful prognostic tool for COPD patients. Future work will be needed to determine whether specific autonomic drugs, like ipratropium, may improve the prognosis in COPD patients with abnormal HRRs.

In summary, spirometry measures of impaired pulmonary function appear to be associated with an abnormal HRR following graded exercise. This observation is consistent with the existence of an important imbalance of autonomic dysfunction in patients with various grades of lung disease. It also suggests that heart rate measures in exercise testing may be useful for routine risk stratification in this clinical setting.


   Footnotes
 
Abbreviations: CI = confidence interval; HRR = heart rate recovery; LLN = lower limits of normal; MET = metabolic equivalent; OR = odds ratio; PFT = pulmonary function test

Dr. Lauer received support from the American Heart Association (grant 0040244N) and the National Heart, Lung, and Blood Institute (grant HL 66004). Dr. Lauer and Ms. Pothier received support from the National Heart, Lung, and Blood Institute (grant HL-66004).

Received for publication May 8, 2003. Accepted for publication October 30, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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