Heart Rate Recovery After Exercise Is a Predictor of Mortality, Independent of the Angiographic Severity of Coronary Disease

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1 Journal of the American College of Cardiology Vol. 42, No. 5, by the American College of Cardiology Foundation ISSN /03/$30.00 Published by Elsevier Inc. doi: /s (03) Heart Rate Recovery After Exercise Is a Predictor of Mortality, Independent of the Angiographic Severity of Coronary Disease Deepak P. Vivekananthan, MD,* Eugene H. Blackstone, MD, FACC, Claire E. Pothier, MA,* Michael S. Lauer, MD, FACC, FAHA* Cleveland, Ohio OBJECTIVES We sought to determine whether abnormal heart rate recovery predicts mortality independent of the angiographic severity of coronary disease. BACKGROUND An attenuated decrease in heart rate after exercise, or heart rate recovery (HRR), has been shown to predict mortality. There are few data on its prognostic significance once the angiographic severity of coronary artery disease (CAD) is ascertained. METHODS For six years we followed 2,935 consecutive patients who underwent symptom-limited exercise testing for suspected CAD and then had a coronary angiogram within 90 days. The HRR was abnormal if 12 beats/min during the first minute after exercise, except among patients undergoing stress echocardiography, in whom the cutoff was 18 beats/min. Angiographic CAD was considered severe if the Duke CAD Prognostic Severity Index was 42 (on a scale of 0 to 100), which corresponds to a level of CAD where revascularization is associated with better long-term survival. RESULTS Severe CAD was present in 421 patients (14%), whereas abnormal HRR was noted in 838 patients (29%). There were 336 deaths (11%). Mortality was predicted by abnormal HRR (hazard ratio [HR] 2.5, 95% confidence interval [CI] 2.0 to 3.1; p ) and by severe CAD (HR 2.0, 95% CI 1.6 to 2.6; p ); both variables provided additive prognostic information. After adjusting for age, gender, standard risk factors, medications, exercise capacity, and left ventricular function, abnormal HRR remained predictive of death (adjusted HR 1.6, 95% CI 1.2 to 2.0; p ); severe CAD was also predictive (adjusted HR 1.4, 95% CI 1.1 to 1.9; p 0.008). CONCLUSIONS Even after taking into account the angiographic severity of CAD, left ventricular function, and exercise capacity, HRR is independently predictive of mortality. (J Am Coll Cardiol 2003;42:831 8) 2003 by the American College of Cardiology Foundation Impaired heart rate recovery (HRR) after exercise predicts mortality (1 3), even after accounting for ischemia (3,4), chronotropic incompetence (1 3,5), and the Duke treadmill score (5). There are few data on its prognostic significance once the angiographic severity of coronary artery disease See page 839 (CAD) is ascertained. In a recent study of male veterans, HRR predicted death, independent of angiographic results, but there was no correlation between HRR and the angiographic severity of disease (6). We examined the association between abnormal HRR and mortality among men and women referred for exercise stress testing and coronary angiography. All-cause mortality was chosen as an unbiased and objective end point (7). From the *Departments of Cardiovascular Medicine, Cardiothoracic Surgery, and Epidemiology and Biostatistics, Cleveland Clinic Foundation, Cleveland, Ohio. This study was funded by Grant HL-66004, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland (Dr. Lauer, Principal Investigator). Manuscript received October 9, 2002; revised manuscript received January 1, 2003, accepted January 11, METHODS Patient population. The cohort was derived from consecutive adults referred for symptom-limited treadmill testing at the Cleveland Clinic Foundation between September 1990 and March All patients were undergoing their first treadmill test at our institution. Patients were eligible if they underwent coronary angiography within 90 days. Exclusion criteria included a history of heart failure, valvular disease, pre-excitation, congenital disease, coronary interventions or surgery, pacemaker placement, use of digoxin, atrial fibrillation, and absence of a recorded U.S. Social Security number. The Cleveland Clinic Foundation s Institutional Review Board approved the performance of research on this clinical data base. Of the 2,935 patients who met these criteria, 1,384 (47%) have been included in previous publications (1,4,5). However, we have not published any data on their angiographic characteristics relation to HRR or whether HRR predicts death in these patients once angiographic data are known. Clinical data. A structured interview and chart review were conducted before each treadmill test regarding symptoms, medications, risk factors, cardiac history, and noncardiac diagnoses (8). Resting hypertension was defined as systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or treatment with antihypertensive medication (9).

2 832 Vivekananthan et al. JACC Vol. 42, No. 5, 2003 Heart Rate Recovery and Coronary Disease September 3, 2003:831 8 Abbreviations and Acronyms CAD coronary artery disease CI confidence interval ESRD end-stage renal disease HR hazard ratio HRR heart rate recovery MET metabolic equivalent PVD peripheral vascular disease Diagnoses of diabetes mellitus and chronic lung disease were determined on the basis of chart review, patient interviews, and medication use. Hypercholesterolemia was defined as a recent total cholesterol value 200 mg/dl or use of a lipid-lowering drug. A history of coronary disease was considered present when there were documented hospitalizations for myocardial infarction or unstable angina. All clinical data, as well as directly measured height and weight, were prospectively recorded on-line. Exercise testing. Symptom-limited exercise testing procedures in our laboratory have been described (10 13). Each patient underwent testing according to standard protocols. Trained exercise physiologists and/or cardiology fellows prospectively collected physiologic and hemodynamic data during testing, including symptoms, heart rate, heart rhythm, blood pressure, and estimated functional capacity in metabolic equivalents (METs; where 1 MET 3.5 ml/kg per min of oxygen consumption). Functional capacity was defined as fair or poor for age and gender, using a previously described scheme (8). Specifically, functional capacity was considered poor among men if it was 8, 7.5, 7, 6, 5.5, 4.5, and 3.5 METs for those age 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 years, respectively. The corresponding values among women were 7.5, 7, 6, 5, 4.5, 3.5, and 2.5 METs. Among men, functional capacity was considered fair if it was not poor and it was 11, 10, 8.5, 8, 7, 5.5, and 4.5 METs for those age 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 years, respectively. The corresponding values among women were 10, 9, 8, 7, 6, 4.5, and 4 METs. We did not consider excellent functional capacity as a separate variable, because in previous work, we found that there were little differences in outcome among patients with average, good, and excellent functional capacity for age and gender (8). A chronotropic response during exercise was defined as the percentage of heart rate reserve used at peak exercise (10). A failure to use 80% of the heart rate reserve defined chronotropic incompetence (10). ST segments were considered abnormal if there was at least 1 mm of horizontal or down-sloping ST-segment depression 80 ms after the J point in at least three consecutive beats in two contiguous leads. Heart rate recovery. Most patients (n 2,426) spent at least 2 min in a cool-down period during treadmill testing at a speed of 2.4 km (1.5 miles) per hour and a grade of 2.5% after achieving peak work load. Those patients who underwent stress echocardiography (n 509) did not have a cool-down period. The value for HRR was defined as the difference in the heart rate from peak exercise to 1 min after peak exercise. Abnormal HRR was defined as 12 beats/min for standard exercise testing and 18 beats/min for patients who underwent stress echocardiography (3). We have previously published prognostically based justifications for these cut-off values (1,3). Coronary angiography. We have described the methods of the coronary angiographic procedures performed in our institution (12,14). Patients were referred for coronary angiography at the discretion of the treating physician. The referring physicians were blinded to the patients HRR values. Cardiologists who were blinded to the patients HRR values and to the hypothesis of this study semiquantitatively analyzed each coronary angiogram. The results were then entered into an angiographic data base. We used the Duke CAD Prognostic Severity Index (15,16) to grade the angiographic severity of CAD. This system assigns a prognostic weight of 0 to 100 based on analyses of the Duke cardiovascular data bank. For example, a value of 0 corresponds to no significant coronary disease, whereas a score of 100 corresponds to 95% left main coronary stenosis. At least one 50% stenotic lesion is required to define the existence of any CAD. Severe CAD was prospectively defined as CAD having a prognostic weight of 42 by the Duke CAD Prognostic Severity Index. This value was chosen because it represents a threshold where mechanical revascularization has been previously shown to reduce mortality rates (15). Left ventricular systolic function was semiquantitatively analyzed by contrast ventriculography or transthoracic echocardiography. We have prognostically validated visual estimates of left ventricular systolic function (3). End points. The primary end point was all-cause mortality during a median of six years of follow-up. Mortality was assessed by using the Social Security Death Master Files (17). In previous work, the Social Security Death Index has been shown to have a very high sensitivity (5) and specificity (18,19). Statistical analyses. Comparisons between patients with and without abnormal HRR were made by using the Wilcoxon rank-sum test for continuous variables and the chi-squared test for categorical variables. The association between HRR and all-cause mortality was assessed by Cox regression analyses (20). Stratified analyses of prespecified subgroups were performed according to the angiographic severity of CAD, gender, age, left ventricular systolic function, functional capacity, exercise-induced angina, ischemic ST-segment changes, or medication usage (including beta-blockers), with formal testing of interaction terms. The Cox proportional hazards assumption was confirmed by inspection of weighted Schoenfeld residuals (21). When evaluating an association within any given data set, the apparent strength of that association may be overesti-

3 JACC Vol. 42, No. 5, 2003 September 3, 2003:831 8 Vivekananthan et al. Heart Rate Recovery and Coronary Disease 833 Table 1. Baseline Characteristics According to HRR Characteristic Normal HRR (>12 beats/min)* (n 2,097) Abnormal HRR (<12 beats/min) (n 838) p Value Age (yrs) Male gender 1,594 (76%) 621 (74%) 0.23 White race 1,863 (89%) 732 (87%) 0.25 Hypertension 926 (44%) 505 (60%) Resting tachycardia ( 100 beats/min) 53 (3%) 72 (9%) Current or recent smoker 407 (19%) 181 (22%) 0.19 Insulin use 88 (4%) 72 (9%) NIDDM 183 (9%) 126 (15%) Hypercholesterolemia 840 (40%) 317 (38%) 0.26 Previous CAD 1,000 (48%) 435 (52%) 0.04 Previous MI 504 (24%) 246 (29%) ACE inhibitor use 244 (12%) 151 (18%) Beta-blocker use 553 (26%) 271 (32%) Aspirin use 832 (40%) 337 (40%) 0.79 Diuretic use 275 (13%) 172 (21%) Nondihydropyridine calcium channel blocker use 193 (9%) 96 (11%) 0.04 Nitrates 570 (27%) 278 (33%) Vasodilators 838 (40%) 435 (57%) Peripheral vascular disease 61 (3%) 35 (4%) 0.08 COPD 56 (3%) 60 (8%) Asthma 57 (3%) 23 (3%) 0.97 ESRD 14 (0.7%) 20 (2%) *For stress echocardiography, 18 beats/min. For stress echocardiography, 18 beats/min. Data are presented as the mean value SD or number (%) of subjects. ACE angiotensin-converting enzyme; CAD coronary artery disease; COPD chronic obstructive pulmonary disease; ESRD end-stage renal disease; HRR heart rate recovery; MI myocardial infarction; NIDDM non insulin-dependent diabetes mellitus. mated because of idiosyncrasies of the data. To correct for this over-optimism, we used a technique called bootstrapping. Here, 250 new data sets were assembled by randomly selecting subjects from the main data set, with the possibility of selecting subjects once, never, or multiple times. Furthermore, each of these new randomly constructed data sets had only 80% of the number of subjects as the main data set, again for the purpose of minimizing the effects of idiosyncratic observations (22,23). A stepwise multivariable Cox regression analysis was performed on each of these 250 data sets, using p 0.10 for model entry and p 0.05 for retention. Those variables that were entered into at least 50% of models were considered for a subsequent set of 1,000 fixed resamplings, which were used for estimation of hazard ratios (HRs) and confidence intervals (CIs). By fixed resamplings, we mean that the Cox models applied to each of these 1,000 bootstrap-generated data sets contained the candidate variables that were entered into 50% of the original models and that no variable selection process was used; all variables were forced in. To assess the association between HRR, considered as a continuous variable, and mortality, we used parametric methods taking into account the possibility of changing the absolute hazard of death over time (24). These enabled us to plot estimated five-year mortality as a function of HRR, exercise capacity, angiographic coronary disease severity, and other variables. We chose to use a parametric approach for this because the use of the Cox regression model for estimation of absolute event risk has been considered by some to be problematic (25,26). The associations of varying angiographic severities of CAD with abnormal HRR were assessed with the chisquared test. The statistical software package SAS version 8.2 (SAS Inc., Cary, North Carolina) was used to perform all of the analyses. Bootstrapping SAS macros were written by Eugene H. Blackstone (available on request). The parametric hazard analyses were performed using the PROC HAZRD, PROC HAZPLOT, and PROC HAZPRED functions. RESULTS Baseline, exercise, and angiographic characteristics. Of 2,935 eligible patients, 838 (29%) had abnormal HRR. Baseline characteristics according to HRR are summarized in Table 1. Patients with abnormal HRR were older, more likely to have hypertension or diabetes, and more likely to have a history of myocardial infarction. Exercise and angiographic characteristics are presented in Tables 2 and 3. Patients with abnormal HRR were more likely to have chronotropic incompetence and less likely to have abnormal ST-segment changes. Severe CAD was present in 421 patients (14%). Patients with abnormal HRR were more likely to have severe CAD (p 0.02). However, abnormal HRR had a sensitivity of only 31% and a specificity of 76% for the detection of any CAD.

4 834 Vivekananthan et al. JACC Vol. 42, No. 5, 2003 Heart Rate Recovery and Coronary Disease September 3, 2003:831 8 Table 2. Exercise Characteristics According to HRR Characteristic Normal HRR (n 2,097) Abnormal HRR (n 838) p Value Peak METs Men Women Poor functional capacity 247 (12%) 203 (24%) Fair functional capacity 537 (26%) 289 (34%) Peak heart rate (beats/min) Chronotropic incompetence 489 (23%) 298 (36%) (no beta-blocker) HRR (beats/min) Angina, non test-limiting 476 (23%) 175 (21%) 0.28 Angina, test-limiting 49 (2%) 18 (2%) 0.75 Abnormal ST-segment changes 578 (28%) 168 (20%) Data are presented as the mean value SD or number (%) of subjects. HRR heart rate recovery; METs metabolic equivalents. Mortality and HRR. During the median follow-up period of six years, there were 336 deaths (11%). Abnormal HRR predicted death (19% vs. 8%; unadjusted HR 2.5, 95% CI 2.0 to 3.1; p ). Of the 336 patients who died, 162 (48%) had an abnormally low HRR. Other univariate predictors of mortality included older age, severe CAD, low ejection fraction, fair or poor functional capacity, a low chronotropic response index, and male gender (Table 4). Abnormal HRR provided additive prognostic information to the angiographic severity of CAD (Fig. 1). There was no interaction between abnormal HRR and the angiographic severity of CAD, gender, age, left ventricular systolic function, functional capacity, exercise-induced angina, or medication usage (including beta-blockers). Multivariable Cox regression analyses. Results of bootstrap resamplings and multivariable Cox regression analyses are shown in Table 5. Variables that entered the final model included age, use of aspirin, abnormal HRR, poor and fair functional capacity, non-test-terminating angina, current or recent smoking, end-stage renal disease (ESRD), low ejection fraction, male gender, resting tachycardia, peripheral vascular disease (PVD), severe CAD, chronotropic incompetence in the absence of a beta-blocker, insulin use, and nifedipine use. After adjustments were made for age, gender, left ventricular function, resting heart rate, chronotropic response index, exercise capacity, exercise-induced angina, ischemic ST-segment depression, the presence or absence of hypertension, diabetes, PVD, hyperlipidemia, tobacco abuse, chronic lung disease, ESRD, the use or nonuse of beta-blockers, nondihydropyridine calcium channel blockers, lipid-lowering therapy, vasodilator medications, and angiographic severity of CAD, a low value for HRR emerged as a strong predictor of death (adjusted HR 1.6, 95% CI 1.2 to 2.0; p ). Even after excluding patients with exercise-induced angina and ischemic ST-segment depression, abnormal HRR was still predictive of mortality (adjusted HR 2.1, 95% CI 1.2 to 3.5; p 0.009). We also performed a stratified analysis according to functional capacity. There were 204 deaths in the 1,276 patients with poor or fair functional capacity. In this group, abnormal HRR strongly predicted the risk of death (HR 2.6, 95% 2.0 to 3.4; p ). In patients with normal functional capacity, abnormal HRR still predicted death, although the association was not as strong (HR 1.7, 95% CI 1.2 to 2.4; p ). There was no interaction between functional capacity and the risk of death associated with abnormal HRR (p 0.07). It is important to note, though, that decreased functional capacity was itself a powerful independent predictor of death (Tables 4 and 5). We also constructed a Cox model in which the CAD severity index was considered as a continuous variable. The Table 3. Angiographic and Ventriculographic Characteristics According to HRR Characteristic Normal HRR (n 2,097) Abnormal HRR (n 838) p Value Duke CAD index 19 (0 32) 23 (0 37) Any CAD 1,279 (61%) 576 (69%) Severe CAD (prognostic score 42) 280 (13%) 141 (17%) 0.02 LMCA disease 79 (4%) 41 (5%) 0.16 Proximal LAD disease 476 (23%) 230 (27%) LCx disease 593 (29%) 282 (34%) RCA/PDA disease 757 (36%) 368 (43%) Low ejection fraction ( 40%) 537 (25%) 269 (32%) Data are presented as the median value (interquartile range) or number (%) of subjects. CAD coronary artery disease; HRR heart rate recovery; LAD left anterior descending; LCx left circumflex coronary artery; LMCA left main coronary artery; PDA posterior descending artery; RCA right coronary artery.

5 JACC Vol. 42, No. 5, 2003 September 3, 2003:831 8 Vivekananthan et al. Heart Rate Recovery and Coronary Disease 835 Table 4. Risk of Death in Prespecified Subgroups on Univariate Analysis Variable HR (95% CI) Chi-Squared Statistic p Value Old age ( 65 yrs) 2.1 ( ) Low CRI (no beta-blocker) 1.9 ( ) Low EF 1.9 ( ) Severe CAD 2.0 ( ) Any CAD 1.9 ( ) Poor functional capacity 2.8 ( ) Low HRR 3.2 ( ) Nondiagnostic ST-segment changes 1.6 ( ) Resting tachycardia ( 100 beats/min) 2.0 ( ) Fair functional capacity 2.0 ( ) Male gender 1.5 ( ) Abnormal ST-segment changes 1.2 ( ) CI confidence interval; CRI chronotropic response index; EF ejection fraction; HR hazard ratio; other abbreviations as in Table 1. association between HRR and death was unchanged. The CAD severity index was also predictive of the risk of death (adjusted HR 1.1 for 20-point increase, 95% CI 1.0 to 1.3; p 0.03). Angiographic severity of CAD, HRR, and mortality in women. There were 720 women (25%), among whom 217 (30%) had abnormal HRR and 62 (9%) had severe CAD. During follow-up, 65 died (9%). Abnormal HRR was independently predictive of death, even after accounting for age, coronary disease severity, functional capacity, ejection fraction, smoking, use of aspirin, and a history of ESRD (adjusted HR 1.5, 95% CI 1.2 to 1.9; p 0.002). Severe angiographic CAD was also an independent predictor of death in women (adjusted HR 1.4, 95% CI 1.1 to 1.9; p 0.01), and its strength of association was similar to that of men. Impact of revascularization. During the first three months after exercise testing, 435 patients (15%) underwent coronary bypass grafting and 368 (13%) underwent percutaneous revascularization. There was no association between having an abnormal HRR and undergoing subsequent bypass grafting (16% vs. 14%, p 0.21) or percutaneous revascularization (13% vs. 12%, p 0.33). However, severe CAD was associated with subsequent coronary artery bypass grafting (45% vs. 10%, p ) but negatively associated with a subsequent percutaneous coronary intervention (10% vs. 13%, p 0.04). After taking into account subsequent revascularization by adding a revascularization Figure 1. Kaplan-Meier plot relating heart rate (HR) recovery and angiographic severity of coronary artery disease (CAD) to risk of death.

6 836 Vivekananthan et al. JACC Vol. 42, No. 5, 2003 Heart Rate Recovery and Coronary Disease September 3, 2003:831 8 Table 5. Results of Cox Multivariate Proportional Model* Variable Percentage of Bootstrap Models Entered Adjusted HR (95% CI) Age (10-yr increase) ( ) Aspirin use ( ) Abnormal HRR ( ) Poor functional capacity ( ) Fair functional capacity ( ) Non-terminating angina ( ) Current or recent smoking ( ) ESRD ( ) Low ejection fraction ( ) Male gender ( ) Resting tachycardia ( ) Peripheral vascular disease ( ) Severe CAD ( ) Chronotropic incompetence (no beta-blocker) ( ) Insulin use ( ) Nifedipine use ( ) *See Methods section of text for details regarding bootstrap resampling methods and modeling techniques. Models in which the variable was retained at p CI confidence interval; HR hazard ratio; other abbreviations as in Table 1. term into a supplementary Cox model, the association between HRR and mortality was unaffected. Type of recovery protocol. There were 509 patients (17%) who underwent stress echocardiography, which mandated assuming a left lateral decubitus position immediately after exercise, as opposed to the more standard upright cooldown. During follow-up, 41 (8.1%) of these patients died. Even after adjusting for age, gender, functional capacity, and angiographic severity of coronary disease, HRR was predictive of mortality among patients undergoing stress echocardiography (adjusted HR 1.9, 95% CI 1.0 to 3.5; p 0.06), similar to patients undergoing other types of testing (adjusted HR 1.9, 95% CI 1.5 to 2.4; p ; p 0.98 for interaction). Parametric analyses. Parametric analyses confirmed an independent association of HRR with mortality, even after accounting for age, gender, left ventricular function, angiographic severity of coronary disease, functional capacity, and other possible confounders. No significant interactions were noted. Figure 2 shows how HRR was associated with predicted five-year mortality as a function of functional capacity. Previously published data. Among the 1,551 patients on whom no HRR data have been published, 450 (29%) had abnormal HRR and 144 died during follow-up. Abnormal HRR was associated with death in unadjusted analyses (16% vs. 7%; unadjusted HR 2.5, 95% CI 1.8 to 3.4; p ) and after adjusting for the severity of coronary disease, along with multiple other confounders (adjusted HR 1.8, 95% CI 1.3 to 2.5; p ). There was no interaction between having been included in a previous publication and the association of HRR with death (p 0.89 for interaction term). Impact of beta-blockers and heart rate-lowering calcium blockers. There were 1,614 patients (55%) who were taking neither beta-blockers nor heart rate lowering calcium blockers. Of these, 405 (25%) had abnormal HRR; during follow-up, 170 died (11%). Abnormal HRR predicted death by itself (19% vs. 8%; unadjusted HR 2.6, 95% CI 1.9 to 3.5; p ) and after adjustment for the severity of coronary disease and other confounders (adjusted HR 1.4, 95% CI 1.0 to 1.9; p 0.04). Of note, among all 2,935 patients, there was no interaction between beta-blocker use and the association of HRR with death (p 0.34 for interaction). Similarly, there was no interaction with calcium channel blocker use (p 0.40 for interaction). Of the 824 patients taking beta-blockers, 231 (28%) had a heart rate 60 beats/min at baseline. Among these patients, the risk of death associated with abnormal HRR was significant (15% vs. 8%; HR 2.1, 95% CI 1.3 to 3.5; p 0.003). The risk of death associated with abnormal HRR did not differ among patients who had a Figure 2. Association of heart rate recovery, considered as a continuous variable, with five-year predicted death rate as a function of exercise capacity. Results of parametric analyses. BPM beats/min; METs metabolic equivalents.

7 JACC Vol. 42, No. 5, 2003 September 3, 2003:831 8 Vivekananthan et al. Heart Rate Recovery and Coronary Disease 837 baseline pulse 60 beats/min (19% vs. 9%; HR 2.2, 95% CI 1.0 to 4.6; p 0.04). DISCUSSION Among patients who had exercise stress testing and who had coronary angiography within 90 days, an attenuated HRR after exercise predicted mortality. The mortality risk of abnormal HRR was comparable to having angiographically severe CAD (15,16). In fact, abnormal HRR provided additive prognostic information to the angiographic severity of CAD. Previously, our group found that abnormal HRR predicted mortality in multiple patient groups (1 5). Only one previous study (6) has evaluated the prognostic significance of abnormal HRR once the angiographic severity of CAD is ascertained. In a male veteran population, Shetler et al. (6) found abnormal HRR to be predictive of increased mortality, independent of the angiographic severity of CAD. Attenuated HRR was not helpful in predicting the presence of significant angiographic coronary disease. Our study confirms and extends these findings in several important respects. First, 25% of our patients were women, among whom HRR predicted death, independent of coronary disease severity, to the same extent as in men. Second, our study included patients who underwent either standard exercise stress testing with a 2-min upright cool-down period or stress echocardiography, which, per protocol, did not have an upright cool-down period. Irrespective of the testing protocol used, we found abnormal HRR to be independently predictive of death, even after accounting for the angiographic severity of coronary disease. Third, we also confirmed that HRR is a poor diagnostic test for angiographic CAD, with a sensitivity of only 31% and a specificity of 76%. Finally, our use of bootstrap resamplings and parametric analyses enabled us to deal with excessive overoptimism inherent when analyzing only one data set and to explore the importance of HRR when considered as a continuous variable. Our study adds to growing evidence that abnormal HRR adversely affects mortality, independent of ischemic burden (1,5). The drop in heart rate after exercise is thought to represent withdrawal of the sympathetic nervous system and, more importantly, reactivation of the parasympathetic nervous system (27,28). Reduced vagal activity has been shown to adversely impact mortality in other patient populations (29,30). At this time, additional study is needed to delineate therapeutic options for patients with abnormal HRR and to determine whether HRR is a modifiable risk factor. To date, no therapy has been systematically investigated for its ability to attenuate the risk associated with abnormal HRR. Preliminary evidence does suggest that cardiac rehabilitation improves HRR (31). Our study was limited because it involved a single tertiary-care referral center and thus was open to biases of patient selection and referral patterns for coronary angiography. Moreover, the use of coronary angiography alone as a risk factor for future cardiac events has been called into question (32). Due to inherent problems of vessel overlap, vessel tortuosity, and vessel resolution, stenoses can be overand/or underestimated. In addition, the degree of luminal stenoses may not correlate with the propensity for plaque rupture. Finally, our study did not identify specific causes of death, but used all-cause mortality as the end point. We found that HRR provides additive prognostic information to the angiographic severity of coronary disease. Our findings provide further evidence supporting the routine incorporation of HRR into exercise testing interpretation. 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