Heart Rate Recovery and Treadmill Exercise Score as Predictors of Mortality in Patients Referred for Exercise ECG (2024)

ContextBoth attenuated heart rate recovery following exercise and the Duketreadmill exercise score have been demonstrated to be independent predictorsof mortality, but their prognostic value relative to each other has not beenstudied.

ObjectiveTo assess the associations among abnormal heart rate recovery, treadmillexercise score, and death in patients referred specifically for exercise electrocardiography.

Design and SettingProspective cohort study conducted in an academic medical center betweenSeptember 1990 and December 1997, with a median follow-up of 5.2 years.

PatientsA total of 9454 consecutive patients (mean [SD] age, 53 [11] years;78% male) who underwent symptom-limited exercise electrocardiographic testing.Exclusion criteria included age younger than 30 years, history of heart failureor valvular disease, pacemaker implantation, and uninterpretable electrocardiograms.

Main Outcome MeasuresAll-cause mortality, as predicted by abnormal heart rate recovery, definedas failure of heart rate to decrease by more than 12/min during the firstminute after peak exercise, and by treadmill exercise score, defined as (exercisetime) − (5 × maximum ST-segment deviation) − (4 ×treadmill angina index).

ResultsThree hundred twelve deaths occurred in the cohort. Abnormal heart raterecovery and intermediate- or high-risk treadmill exercise score were presentin 20% (n = 1852) and 21% (n = 1996) of patients, respectively. In univariateanalyses, death was predicted by both abnormal heart rate recovery (8% vs2% in patients with normal heart rate recovery; hazard ratio [HR], 4.16; 95%confidence interval [CI], 3.33-5.19; χ² = 158; P<.001) and intermediate- or high-risk treadmill exercise score(8% vs 2% in patients with low-risk scores; HR, 4.28; 95% CI, 3.43-5.35; χ² = 164; P<.001). After adjusting for age,sex, standard cardiovascular risk factors, medication use, and other potentialconfounders, abnormal heart rate recovery remained predictive of death (amongthe 8549 patients not taking β-blockers, adjusted HR, 2.13; 95% CI, 1.63-2.78; P<.001), as did intermediate- or high-risk treadmillexercise score (adjusted HR, 1.49; 95% CI, 1.15-1.92; P = .002). There was no interaction between these 2 predictors.

ConclusionsIn this cohort of patients referred specifically for exercise electrocardiography,both abnormal heart rate recovery and treadmill exercise score were independentpredictors of mortality. Heart rate recovery appears to provide additionalprognostic information to the established treadmill exercise score and shouldbe considered for routine incorporation into exercise test interpretation.

Attenuated heart rate recovery after exercise, which is thought to bea marker of reduced parasympathetic activity,^1,2has been shown to be an independent predictor of mortality among patientsreferred for stress nuclear testing³ and amonghealthy adults enrolled in a population-based cohort study.⁴The Duke treadmill exercise score, a composite of measures of functional capacityand stress-induced ischemia, has been shown to predict mortality risk in differentpatient subsets.^5-7It is unknown, however, whether or how heart rate recovery and the treadmillexercise score relate to each other as prognostic measures. The purpose ofthis study was to determine whether heart rate recovery adds to or interactswith the treadmill exercise score as a predictor of all-cause mortality⁸ among patients referred for exercise electrocardiography(ECG).

The study population consisted of consecutive patients referred specificallyfor exercise ECG at the Cleveland Clinic Foundation between September 1990and December 1997. Patients were excluded if they were younger than 30 yearsold, had a history of heart failure, valvular or congenital disease, or hadpacemaker implantation. No patients had uninterpretable ST segments due toleft bundle-branch block, digoxin use, preexcitation syndrome, left ventricularhypertrophy, or more than 1 mm of resting ST-segment depression, and no patientswere undergoing concurrent imaging studies. Patients were excluded if a validSocial Security number was not available or if they lived outside the UnitedStates. The protocol was approved by the foundation's institutional reviewboard.

Prior to exercise testing, each patient underwent a structured historytaking and medical record review to document symptoms, past medical history,medication use, cardiac risk factors, and prior cardiac events and procedures.⁹ Patients were considered to be undergoing screeningtests if they had no symptoms suggestive of coronary heart disease and hadno notable cardiac history.

Resting tachycardia was considered present if the resting heart ratewas 100/min or greater. Hypertension was defined as systolic blood pressureof 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, oruse of antihypertensive medications.¹⁰ Diabeteswas defined as documented prescription of a diabetic diet or use of insulinor other hypoglycemic medications. Prior coronary artery disease was consideredpresent if diagnosed by prior coronary angiography; if there was a documentedhistory of revascularization, myocardial infarction, or unstable angina; orif pathologic Q waves were present in at least 2 contiguous ECG leads. Totalcholesterol values were routinely recorded if obtained within the previous3 months and if they were 200 mg/dL (5.18 mmol/L) or higher. Hypercholesterolemiawas defined as a documented total cholesterol level of 200 mg/dL (5.18 mmol/L)or higher or the use of lipid-lowering medications. Chronic obstructive pulmonarydisease was based on documentation in the medical record or use of inhaledor oral bronchodilators. Patients were considered smokers if they regularlysmoked cigarettes within the past year.

To describe pretest risk of prognostically significant coronary arterydisease, we used a validated Mayo Clinic risk index in which 1 point was addedfor each of the following: male sex, typical angina pectoris, prior myocardialinfarction by history or ECG, diabetes, and insulin use.¹¹

All clinical and exercise data were recorded prospectively into a computerizeddatabase.⁹ All data fields were standardizedwith prespecified definitions; all personnel involved with administering testswere formally trained how to complete data fields. For quality control, weperiodically performed random comparisons of exercise reports with chart reviews.

Patients underwent "symptom-limited" exercise treadmill testing usingprimarily Bruce or modified Bruce protocols.¹²Predicted peak heart rate was calculated as 220 − age. Patients wereencouraged to exercise until they experienced limiting symptoms, even if 85%of maximum predicted heart rate was achieved. During each exercise stage andrecovery stage, symptoms (eg, chest discomfort, shortness of breath, fatigue,dizziness, leg pain, and heart palpitations), blood pressure, heart rate,cardiac rhythm, and exercise workload in metabolic equivalents (METs) wererecorded. An ischemic ST-segment response was defined as at least 1 mm ofhorizontal or downsloping ST-segment depression 80 milliseconds after theJ point.

Following peak exercise, patients walked for a 2-minute cool-down periodat 1.5 mph at a 2.5% grade. Heart rate recovery was defined as the differencebetween heart rate at peak exercise and 1 minute later. A cutoff value of12/min or less was considered abnormal, based on a previous study from ourlaboratory that involved a different cohort.³Chronotropic incompetence was considered present if less than 80% of the patient'sheart rate reserve (calculated as 220 − age − resting heart rate)was used at peak exercise.^13,14

The Duke treadmill exercise score was calculated as previously described:[duration of exercise (in minutes)] − [5 × maximal ST-segmentdeviation during or after exercise (in millimeters)] − [4 × treadmillangina index (0 = no angina, 1 = nonlimiting angina, 2 = exercise-limitingangina)]. A treadmill exercise score of 5 or greater was considered low risk;–10 to +4, intermediate risk; and less than –10, high risk.^5-7

Patients were followed up for a median of 5.2 years (range for survivors,1.4-8.7 years) through May 1999. The primary end point was all-cause mortalityas reported by the Social Security Death Index,¹⁵which has been shown to be more specific and possibly less biased than theNational Death Index.¹⁶ Unlike "cardiac mortality,"all-cause mortality is an objective and unbiased end point.⁸

The high specificity, exceeding 99%, of the Social Security Death Indexhas been established.¹⁷ To assess the likelysensitivity of this index in our population, we analyzed the outcomes of 873patients who had undergone coronary artery bypass graft surgery and had subsequentlyan exercise thallium study at our institution between 1990 and 1993.¹⁸ Vital status was ascertained by contacting all patientsor next of kin through 1998. There were 102 confirmed deaths linked to a SocialSecurity number; of these, the Social Security Death Index correctly identifiedthe decedent status of 99 (sensitivity, 97%, 95% confidence interval [CI],91%-99%).

The univariate associations of abnormal heart rate recovery, an intermediate-or high-risk treadmill exercise score, chronotropic incompetence, and otherpotential predictors of death were assessed using Kaplan-Meier curves¹⁹ and Cox proportional hazards models.²⁰Analyses of heart rate recovery and treadmill exercise score as continuousvariables included tests of logarithmically transformed values. The Cox proportionalhazards assumption was confirmed by examination of log (−log[survival])curves. Additional analyses were performed to assess potential interactionswith certain prespecified candidate covariates, including age, sex, use of β-blockers,use of calcium channel antagonists, smoking, hypertension, diabetes, knowncoronary artery disease, chronotropic incompetence, testing for screening,and abnormal treadmill exercise score. If an interaction was found, specificterms describing the concurrent presence of factors were defined such thatseparate hazard ratios could be estimated according to the presence of theeffect-modifying factor.

An additional set of Cox analyses was performed to confirm the validityof the estimates for the model in which all exercise variables were consideredin dichotomous terms. A series of bootstrap resamplings were performed.^21,22 First, 250 resampling analyses weredone for variable selection, using P = .10 for modelentry and P≤.05 for retention. Second, those variablesthat were still retained in at least half the models were considered in 1000fixed variable resamplings.

All analyses were performed using SAS version 6.12 software (SAS Inc,Cary, NC). Bootstrapping was performed using SAS macros written by one ofus (E.H.B.; available on request).

The study cohort consisted of 9454 patients. The median value of heartrate recovery was 19/min, with 25th and 75th percentile values of 14/min and24/min, respectively. Twenty percent of the population (n = 1852) had abnormalheart rate recovery, and 21% (n = 1996) had an intermediate- to high-risktreadmill exercise score. Only 25 patients (<1%) had a high-risk treadmillexercise score, so they were considered together with patients with an intermediatescore. There were 3565 potentially eligible patients who either did not havevalid Social Security numbers recorded or lived outside the United States.Those patients had nearly identical distributions of age, functional capacity,ST-segment responses, and heart rate recovery as study patients.

Baseline characteristics of the study population are shown in Table 1. Patients with abnormal heart raterecovery had more adverse risk profiles. Cholesterol data were available inabout 25% of patients, irrespective of heart rate recovery; there was no associationbetween heart rate recovery and cholesterol level.

Exercise characteristics according to heart rate recovery are summarizedin Table 2. Patients with abnormalheart rate recovery had lower functional capacity and lower peak heart rates,and they used less of their heart rate reserve at peak exercise. The 2 groups(abnormal and normal heart rate recovery) were similar with regard to measuredST-segment depression, ST-segment slope interpretation, and non–test-limitingangina.

During a median follow-up of 5.2 years, there were 312 deaths. The presenceof abnormal heart rate recovery was strongly associated with death (8% vs2% in patients with normal heart rate recovery; hazard ratio [HR], 4.16; 95%CI, 3.33-5.19; χ² = 158, P<.001).Other univariate predictors of mortality included resting tachycardia (9%vs 3% in patients without tachycardia; HR, 2.76; 95% CI, 1.95-3.91; χ² = 33, P<.001), an intermediate- or high-risktreadmill exercise score (8% vs 2% in patients with low-risk scores; HR, 4.28;95% CI, 3.43-5.35; χ² = 164, P<.001),and chronotropic incompetence (9% vs 2% in patients without chronotropic incompetence;HR, 4.68; 95% CI, 3.74-5.84; χ² = 184, P<.001).

Stratified analyses relating normal and abnormal values for heart raterecovery to death among prespecified subgroups are shown in Table 3. Abnormal heart rate recovery was associated with deathin all subgroups except for patients taking β-blockers. Abnormal heartrate recovery provided additive prognostic information to the treadmill exercisescore, with no interaction noted (Table3 and Figure 1).

Heart rate recovery also was predictive of mortality when consideredas a continuous variable. Heart rate recovery values less than 10/min to 12/minwere associated with increasing risk of death (Figure 2).

In multivariate proportional hazards analyses, adjusting for potentialconfounders (listed in the footnote to Table 4), abnormal heart rate recovery was predictive of death.There were no interactions noted between heart rate recovery and either thetreadmill exercise score or chronotropic incompetence; however, a significantinteraction was noted such that heart rate recovery was not predictive ofdeath among patients taking β-blockers. An intermediate- to high-risktreadmill exercise score and chronotropic incompetence were also predictiveof mortality. There was no interaction noted between the treadmill exercisescore and β-blocker use. When the 25 patients with an exercise treadmillscore lower than −10 were excluded, the results were essentially unchanged.

When heart rate recovery and the exercise treadmill score were analyzedas continuous variables, similar results were noted; model fit was improvedwith logarithmic transformation of heart rate recovery, but not of treadmillexercise score. When the 3 components of the treadmill exercise score wereanalyzed separately, functional capacity was predictive of death (for each2.5-MET decrease: adjusted HR, 1.57; 95% CI, 1.33-1.85; P<.001), but ST-segment changes (for each additional 1 mm of ST-segmentdepression: adjusted HR, 1.09; 95% CI, 0.93-1.29; P= .30) and exercise-induced angina (adjusted HR, 1.14; 95% CI, 0.69-1.89; P = .62) were not. In this model, the association betweenheart rate recovery and death was similar to the primary model shown in Table 4.

In 250 bootstrap resamplings, the only variables that entered at least50% of models were age (100%), chronotropic incompetence (97%), resting tachycardia(97%), heart rate recovery (96%), current or recent smoking (96%), the treadmillexercise score (79%), sex (76%), and use of vasodilators (74%). No interactionterm, including the β-blocker interaction term, entered even 50% of models.After 1000 subsequent fixed-model resamplings, abnormal heart rate recoverywas still predictive of death (adjusted HR, 1.77; 95% CI, 1.39-2.28), as waschronotropic incompetence (adjusted HR, 2.13; 95% CI, 1.62-2.72) and a high-or intermediate-risk treadmill exercise score (adjusted HR, 1.52; 95% CI,1.16-2.03).

Among 7095 patients who were referred for screening exercise tests,179 (3%) died during 5 years of follow-up. Abnormal heart rate recovery predicteddeath just as well in this group as among nonscreening patients (Table 3). Abnormal heart rate recoveryas an isolated finding was noted in 709 patients (10%), among whom 28 (4%)died (age- and sex-adjusted HR, 2.73; 95% CI, 1.71-4.34; P<.001). An additional 469 patients (7%) had abnormal heart raterecovery along with either chronotropic incompetence or a high- or intermediate-risktreadmill exercise score; 50 (11%) of these patients died (adjusted HR, 4.43;95% CI, 2.88-6.81; P<.001).

Of 2123 women, 68 (3%) died. Heart rate recovery was associated withdeath in women, but there was no sex interaction noted (Table 3). Abnormal treadmill exercise score also was predictiveof death (6% vs 2%; HR, 4.43; 95% CI, 2.69-7.29; P<.001).In a multivariate model independent predictors of mortality included abnormalheart rate recovery (adjusted HR, 2.73; 95% CI, 1.66-4.50; P<.001), age (for each 10 years, adjusted HR, 1.96; 95% CI, 1.54-2.48; P<.001), and Mayo risk index (for each additional riskfactor, adjusted HR, 1.60; 95% CI, 1.20-2.13; P =.001). The treadmill exercise score was not independently predictive.

There were 4060 patients (43%) who achieved 100% or more of their age-predictedmaximum heart rate. Among these, 70 patients (2%) died; abnormal heart raterecovery was associated with death (5% vs 1%; HR, 4.26; 95% CI, 2.65-6.68; P<.001). In a multivariate model the only independentpredictors of mortality were age (for each 10 years, adjusted HR, 3.65; 95%CI, 2.82-4.73; P<.001) and abnormal heart raterecovery (adjusted HR, 2.30; 95% CI, 1.41-3.77; P<.001);the treadmill exercise score was not independently predictive.

Among patients referred for exercise ECG, heart rate recovery was astrong and independent predictor of all-cause mortality. Furthermore, heartrate recovery gave additional prognostic information over and above the Duketreadmill exercise score.

Multiple exercise variables obtained during stress testing have beenassessed for prognostic value.^5,23-29The treadmill exercise score is an established exercise assessment that considersthe duration of exercise, ST-segment deviation, and angina during exercise.^5-7 Exercise heart rateresponse variables, specifically heart rate recovery and chronotropic incompetence,have been shown to have prognostic value.^3,4,14,30-32We have demonstrated that heart rate recovery was a predictor of mortalityin a moderate-risk population undergoing symptom-limited exercise thalliumtesting.³ We also have found heart rate recoveryto be predictive of death among healthy individuals in a population-basedcohort study undergoing submaximal exercise testing.⁴

The current study extends previous findings in several respects. First,it confirms the prognostic value of heart rate recovery as a strong and independentpredictor of mortality in a cohort of patients referred specifically for exerciseECG; our cohort is likely to be similar to patients seen in general medicalpractice. Of note, despite the very different risk profile of the populationstudied, the association between the level of heart rate recovery, assessedas a continuous variable (Figure 2),and risk of death was similar to that of the higher-risk population studiedpreviously.³ When heart rate recovery decreasesto less than 10/min to 12/min, risk of death increases markedly.

Second, heart rate recovery, along with treadmill exercise score andchronotropic response, were found to predict mortality among adults undergoingscreening exercise testing, which is a controversial practice.³³Our study suggests that by using heart rate response and treadmill exercisescore, exercise tests can be used as a powerful marker of risk even in healthypatients. In fact, there was no difference in the predictive properties ofheart rate recovery in the screening and symptomatic groups.

Third, heart rate recovery further risk-stratified patients over andabove the treadmill exercise score. Patients with intermediate- to high-risktreadmill exercise scores were found to have even higher mortality if abnormalheart rate recovery was also present (Figure1). Patients with both low-risk treadmill exercise scores and normalheart rate recovery had very low risk of death.

We found that heart rate recovery was not predictive of mortality amongpatients taking β-blockers, which contrasts with our previous observationin a different, higher-risk population.³ Thisobservation must be interpreted with caution given the small number of eventsthat occurred among patients taking β-blockers and the failure of the β-blockerinteraction term to be validated in a rigorous bootstrap analysis.

The mechanisms of adverse outcome associated with abnormal heart raterecovery are unclear. Parasympathetic activation is thought to be the underlyingmechanism of heart rate recovery after exercise,^1,2and abnormalities in parasympathetic activation have been suggested as thelink to mortality.³ Together, heart rate recoveryand treadmill exercise score appear to be complementary, strengthening thepredictive value of exercise stress testing.

Our current study has several limitations. It was an observational,single-center experience, and it is not known if heart rate recovery is amodifiable risk factor. In addition, we had incomplete data on lipid abnormalities;only total cholesterol values were available for those patients who had bloodsamples drawn within 3 months of exercise testing and high-density lipoproteincholesterol values were not recorded. Thus, we could not use the Framinghamcoronary heart disease index³⁴ to control forbaseline risk. Nonetheless, we found little if any association between lipidabnormalities and heart rate recovery. Previously we found no associationbetween lipid abnormalities and heart rate recovery,⁴so it is unlikely that the association between heart rate recovery and mortalitywas materially confounded by lipid disorders.

Heart rate recovery was a strong and independent predictor of mortalityamong patients referred for exercise ECG. Heart rate recovery provides additionalprognostic information to the established treadmill exercise score and shouldbe considered for routine incorporation into exercise test interpretation.