Patient Population

The study cohort was made up of consecutive adult patients who were referred to the Cleveland Clinic Foundation for a first symptom-limited exercise test and single-photon-emission computed tomography with thallium scintigraphy between September 1990 and December 1993.8,9 We included patients who were candidates for initial angiography.10 Patients were excluded if they had a history of coronary angiography, previous cardiac surgery, an implanted pacemaker, congestive heart failure or use of digoxin, congenital or valvular heart disease, the preexcitation syndrome, or left bundle-branch block (because of the potential for false positive findings of myocardial perfusion defects on thallium scintigraphy during exercise in patients with these factors). Patients were also excluded if a valid Social Security number was not included in their registration or if data on the recovery of heart rate were not available. All patients gave informed consent before testing; the protocol was approved by the institutional review board of the Cleveland Clinic Foundation.

Clinical Data

Before the patients were tested, a review of each patient's chart and a structured interview were conducted to gather data on symptoms, medications, coronary risk factors, previous cardiac events, and other diagnoses.9 Hypertension was defined as a systolic blood pressure of ≥140 mm Hg at rest, a diastolic blood pressure of ≥90 mm Hg at rest, or treatment with antihypertensive medication.11 Diagnoses of diabetes mellitus and chronic lung disease were determined on the basis of chart review, interviews with the patients, and use of medication by the patients. A history of coronary disease was considered present when there were documented hospitalizations for myocardial infarction or unstable angina. The presence of a lipid disorder was defined by the use of lipid-lowering medication at the time of testing. Cardioactive medications were classified as beta-blockers, nondihydropyridine calcium-channel blockers (e.g., diltiazem and verapamil), or vasodilators (e.g., nifedipine, alpha-adrenergic blockers, and angiotensin-converting–enzyme inhibitors).

Exercise Testing

Exercise testing of most of the patients was conducted according to the standard and modified Bruce protocols.12 Whether cardioactive medications were used on the day of the test was left to the discretion of the referring physician. So that workload could be more accurately estimated, the patients were not allowed to lean on the handrails. Midway through each stage of exercise, at peak exercise, and one minute after the cessation of exercise, data on symptoms, heart rate and rhythm, blood pressure (as measured by indirect arm-cuff sphygmomanometry), and estimated workload (as determined on the basis of standard tables)12 in metabolic equivalents (MET; 1 MET equals 3.5 ml of oxygen uptake per kilogram of body weight per minute) were collected and entered into a computer data base. The patients were encouraged to reach symptom-limited maximal exercise; the achievement of the target heart rate (based on age) alone was not a sufficient reason for the termination of testing. Chronotropic response during exercise was defined as the percentage of the heart-rate reserve (the difference between the maximal achievable heart rate [220 beats per minute minus age in years] and the resting heart rate) used at peak exercise. A failure to use 80 percent of the heart-rate reserve was considered to be evidence of an impaired chronotropic response.13 This measure is an independent predictor of mortality.8

Recovery of Heart Rate

After achieving peak workload, all the patients spent at least two minutes in a cool-down period during treadmill testing at a speed of 2.4 km (1.5 mi) per hour and a grade of 2.5 percent. This period was considered the recovery period. The value for the recovery of heart rate was defined as the reduction in the heart rate from the rate at peak exercise to the rate one minute after the cessation of exercise.

We determined an abnormal value for the recovery of heart rate by finding the maximal value for the log-rank chi-square test statistic for all possible cutoff points between the 10th and 90th percentiles for the study cohort.14 A secondary abnormal value was based on the value for the 10th percentile for the study cohort.

Thallium Scintigraphy

The scintigraphic methods used in our laboratory between 1990 and 1993 have been described in detail elsewhere.15 We determined a modified summed score on the thallium stress test for each patient by dividing the number of segments of the left ventricle with either fixed or reversible perfusion defects during thallium scintigraphy by the total number of segments. We have previously reported on the associations between such defects and mortality.8,9,16

End Points

The mean follow-up time was six years. The primary end point was death from all causes, identified through a search of the Social Security death index by Epidemiology Resources (Newton, Mass.). This index has previously been validated and is slightly less sensitive but more current and specific than the National Death Index.17

Statistical Analysis

For descriptive purposes, the patients were divided into two groups on the basis of the value for the recovery of heart rate. Continuous variables are presented as means ±SD. Differences between groups were compared with the use of Student's t-test, Wilcoxon's rank-sum test, and the chi-square test, as appropriate.

The value for heart-rate recovery was related to mortality from all causes by univariable and multivariable Cox regression analyses.18 We performed stratified analyses of prespecified subgroups defined according to age, sex, history of coronary disease, the chronotropic response during exercise, the presence or absence of perfusion defects on thallium scintigraphy, and the use or nonuse of medications. Logarithmic and quadratic transformations and potential interactions were assessed for improvement of fit. To assess further the association of heart-rate recovery with mortality, the population was divided according to quintiles of values for recovery, with relative risks and confidence intervals calculated on the basis of comparisons with the highest quintile. The Cox proportional-hazards assumption was confirmed by inspection of log [–log (survival function)] curves.

To assess the association between heart-rate recovery and exercise capacity, the study cohort was divided into sex-specific deciles of exercise capacity, measured in MET. Differences in the proportion of patients with an abnormal value for heart-rate recovery (≤12 beats per minute) were compared with use of the chi-square test for trend.19 Logistic-regression analysis was used to assess the effects of exercise capacity and medications on heart-rate recovery after adjustment for age, sex, and the presence or absence of perfusion defects on thallium scintigraphy.20 All analyses were performed with the SAS statistical package (version 6.12, SAS Institute, Cary, N.C.).