Prognostic Value of Late Heart Rate Recovery After Treadmill Exercise

Transcription

1 Prognostic Value of Late Heart Rate Recovery After Treadmill Exercise Nils P. Johnson, MD, MS a and Jeffrey J. Goldberger, MD b, * Recovery from exercise can be divided into an early, rapid period and a late, slower period. Although early heart rate (HR) recovery 1 minute after treadmill exercise independently predicts survival, the prognostic value of late HR recovery has not been well studied. The aim of this study was to evaluate the independent prognostic value of late HR recovery for all-cause mortality. A total of 2,082 patients referred to the nuclear cardiology laboratory of an urban academic medical center for treadmill exercise with imaging from August 1998 to December 2003 were followed for all-cause mortality. During years of follow-up, 196 deaths (9%) occurred. To avoid overlap with early HR recovery or the baseline HR, late HR recovery was defined as the percentage of the cycle length change between rest and peak exercise that had been recovered after 5 minutes. Lower values represent impaired recovery, by analogy with 1-minute HR recovery. Impaired late HR recovery was a significant univariate predictor of all-cause mortality (hazard ratio 0.28 per percentage, 95% confidence interval 0.17 to 0.46, p <0.001). It significantly improved a nested, multivariate model (change in chi-square 8.66, p 0.003), including 1-minute HR recovery, with independent prognostic value (adjusted hazard ratio 0.58, 95% confidence interval 0.41 to 0.84, p 0.004). In conclusion, late HR recovery after treadmill exercise stress adds prognostic value for all-cause mortality to a multivariate model including early, 1-minute HR recovery Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:45 49) Heart rate (HR) response at the start of exercise, 1 and its recovery in the early post-exercise recovery period, 2 6 have been shown to be independent prognostic factors for survival. However, complete HR recovery after exercise extends well beyond the 1-minute mark and is a complex interplay among intrinsic, sympathetic, and parasympathetic components. 7 The prognostic impact of the later component of HR recovery after exercise has received limited study Therefore, we hypothesized that incorporating late HR response would improve prediction of all-cause survival when added to early (1-minute) recovery. We specifically focused on overall mortality as an unbiased, objective end point. Methods The study was approved by the institutional review board of Northwestern University. Our cohort consisted of patients referred to our nuclear cardiology laboratory for a treadmill exercise stress study with single-photon emission computed tomographic (SPECT) perfusion imaging. Inclusion criteria were age 18 years, a study performed from August 1998 to December 2003 (to ensure the availability of archived and decipherable digitized electrocardiographic (ECG) waveforms), and available ECG tracings at peak exercise and at 1 and 5 minutes into recovery. Exclusion criteria were missing Social Security number, a previous included study (only the first of multiple studies was included), or an increase in heart rate of 10% between serial tracings during recovery. Allcause mortality was determined from the Social Security Administration Death Master File. 11 Length of survival was computed as the number of days between the treadmill exercise stress test and the date of death or the end of December 2010, whichever came first. All patients had 7 years of follow-up. Available demographic and clinical information included age, sex, previous mechanical revascularization, classic risk factors, body mass index, and current cardiac medications. Bruce protocol treadmill exercise duration, treadmill-induced angina, and peak blood pressure were recorded. In contrast to previous work, 2 our exercise laboratory does not use a formal 2-minute cool-down period, although patients continue on the treadmill for approximately 30 seconds after peak exercise before the belt stops. Rest, stress, and recovery 12-lead ECG tracings were interpreted using standard criteria. 12 Most SPECT studies used a single-day dual-isotope protocol. 13 Rest images were acquired using intravenous thallium- 201 and stress images with technetium-99m sestamibi. A minority of studies used a 2-day technetium-99m sestamibi protocol in patients weighing 350 lb to improve image quality. Images were interpreted using a 20-segment scoring system in which 0 normal tracer activity and 4 no tracer activity. 13 Total scores for the stress and rest images determined the summed stress score and summed rest score, respeca Weatherhead PET Center For Preventing and Reversing Atherosclerosis, Division of Cardiology, Department of Medicine, University of Texas Medical School and Memorial Hermann Hospital, Houston, Texas; and b Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Manuscript received December 14, 2011; revised manuscript received and accepted February 21, This study was supported in part by Grant 1 RO1 HL A2 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr. Goldberger is the director of Path to Improved Risk Stratification, a not-for-profit think tank on risk stratification for sudden cardiac death. *Corresponding author: Tel: ; fax: address: j-goldberger@northwestern.edu (J.J. Goldberger) /12/$ see front matter 2012 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 46 The American Journal of Cardiology ( Table 1 Cohort characteristics and univariate predictors of survival Variable Cohort (n 2,082) Alive (n 1,886) Dead (n 196) p Value* p Value Age (years) ( ) Men 1,187 (57%) 1,061 (56%) 126 (64%) ( ) Hypertension 764 (37%) 659 (35%) 105 (54%) ( ) Dyslipidemia (by history or 902 (43%) 812 (43%) 90 (46%) ( ) 0.34 prescribed medications) Diabetes mellitus 238 (11%) 189 (10%) 49 (25%) ( ) Previous or current tobacco use 279 (13%) 246 (13%) 33 (17%) ( ) 0.08 Family history of coronary disease 554 (27%) 514 (27%) 40 (20%) ( ) 0.07 Body mass index (kg/m 2 ) 27 (24 31) 27 (24 31) 27 (24 32) ( ) 0.49 Previous mechanical revascularization 262 (13%) 208 (11%) 54 (28%) ( ) Antiplatelet medications 635 (30%) 550 (29%) 85 (43%) ( ) blockers 458 (22%) 387 (21%) 71 (36%) ( ) Angiotensin-converting enzyme 283 (14%) 238 (13%) 45 (23%) ( ) inhibitors Anticholesterol medications 625 (30%) 553 (29%) 72 (37%) ( ) Calcium channel blockers 224 (11%) 187 (10%) 37 (19%) ( ) Diuretics 233 (11%) 190 (10%) 43 (22%) ( ) Antihypertensive medications 220 (11%) 196 (10%) 24 (12%) ( ) 0.30 Exercise time (minutes) ( ) Double product (mm Hg/min) 28,392 5,242 28,676 5,128 25,668 5, ( ) Treadmill angina 118 (6%) 106 (6%) 12 (6%) ( ) 1.00 Treadmill ECG changes 461 (22%) 407 (22%) 54 (28%) ( ) Summed difference score 0 (0 2) 0 (0 2) 0 (0 4) ( ) Transient cavity dilation 101 (5%) 86 (5%) 15 (8%) ( ) Ejection fraction (%) ( ) Rest HR (beats/min) ( ) Peak HR (beats/min) ( ) minute HR recovery (beats/min) ( ) Late HR recovery (%) 42% (31% 51%) 42% (32% 51%) 35% (24% 44%) ( ) Data are expressed as mean SD, number (percentage), or median (interquartile range). * Comparison between alive and dead. Hazard ratio from univariate Cox model. Linear term hazard ratio listed, squared term 1.00 (95% confidence interval 1.00 to 1.00, p 0.43). Linear term hazard ratio listed, squared term 1.06 (95% confidence interval 1.01 to 1.12, p 0.03). tively, the difference of which represents the combined size and severity of stress-induced perfusion defects. Most stress SPECT images were electrocardiographically gated to yield the left ventricular ejection fraction, although arrhythmia limited gating in a minority of patients. Transient cavity dilatation was reported on the basis of a combination of visual assessment and software-reported ratio. ECG waveforms in digital format were extracted from our Marquette MUSE database (GE Healthcare, Milwaukee, Wisconsin) using custom software. These tracings provide 10 seconds of data in standard 12-lead arrangement. The Marquette software recorded the HR in beats per minute for each tracing, from which the RR interval in milliseconds was calculated. The HRs at baseline, peak exercise, and 1 and 5 minutes into recovery were recorded in beats per minute and converted to RR intervals in milliseconds (60,000/HR [beats/min]). Assessing late HR recovery requires careful definition of the variable to study. The simple definition of peak HR minus HR at 5 minutes into recovery is unsuitable for several reasons. First, there is a high degree of correlation between this variable and standard 1-minute HR recovery (in our cohort, Pearson s r for the relation between 1- and 5-minute HR recovery defined in this manner), because a large component of 5-minute HR recovery occurs in the first minute. Furthermore, in late recovery, the HR trends toward the rest values. Thus, the difference between peak and late HR predominantly reflects rest and peak HR values. To provide an independent index of late HR recovery, we therefore assessed the percentage HR recovery. Late HR recovery at 5 minutes was defined as [1 (RR 5min RR peak )/(RR rest RR peak )] 100. This gives the percentage of the cycle length change between rest and peak exercise that has been recovered after 5 minutes. Lower values represent impaired recovery, by analogy with 1-minute HR recovery. In our cohort, the correlation between 1-minute HR recovery and this definition of late HR recovery at 5 minutes was not significant (Pearson s r , p 0.43), establishing it as a suitable parameter of late HR recovery for evaluation. Late HR recovery was optimally dichotomized into normal and abnormal groups by maximizing the log likelihood ratio from a Cox proportional-hazards model with the limitation that each subgroup had 10% of the cohort. 6 All statistical tests were performed using R version 2.13 (R Project for Statistical Computing, Vienna, Austria) with missing data (6% of 6 affected variables) imputed by the MI

3 Coronary Artery Disease/Late Heart Rate Recovery 47 Table 2 Cohort characteristics by quartile of late heart rate recovery Variable Quartile 1 Quartile 2 Quartile 3 Quartile 4 p Value Late HR recovery 22% (13% 27%) 37% (34% 39%) 46% (44% 48%) 56% (53% 61%) NA Number of patients 521 (25%) 520 (25%) 521 (25%) 520 (25%) NA Number of deaths 73 (14%) 61 (12%) 38 (7%) 24 (5%) Age (years) Men 199 (38%) 263 (51%) 321 (62%) 404 (78%) Hypertension 210 (40%) 196 (38%) 194 (37%) 164 (32%) Dyslipidemia 210 (40%) 228 (44%) 241 (46%) 223 (43%) 0.28 Diabetes mellitus 82 (16%) 63 (12%) 53 (10%) 40 (8%) Previous or current tobacco use 67 (13%) 71 (14%) 76 (15%) 65 (12%) 0.76 Family history of coronary disease 139 (27%) 146 (28%) 136 (26%) 133 (26%) 0.82 Body mass index (kg/m 2 ) 27 (24 31) 28 (25 32) 27 (25 31) 27 (24 31) 0.12 Previous mechanical revascularization 57 (11%) 63 (12%) 76 (15%) 66 (13%) 0.35 Antiplatelet medications 158 (30%) 173 (33%) 147 (28%) 157 (30%) 0.36 blockers 111 (21%) 105 (20%) 114 (22%) 128 (25%) 0.36 Angiotensin-converting enzyme 72 (14%) 59 (11%) 81 (16%) 71 (14%) 0.27 inhibitors Anticholesterol medications 144 (28%) 150 (29%) 170 (33%) 161 (31%) 0.30 Calcium channel blockers 76 (15%) 59 (11%) 47 (9%) 42 (8%) Diuretics 72 (14%) 64 (12%) 54 (10%) 43 (8%) Antihypertensive medications 60 (12%) 57 (11%) 57 (11%) 46 (9%) 0.52 Exercise time (minutes) Double product (mm Hg/min) 26,642 5,280 27,911 5,010 29,217 4,996 29,795 5, Treadmill angina 35 (7%) 32 (6%) 29 (6%) 22 (4%) 0.34 Treadmill ECG changes 106 (20%) 109 (21%) 117 (22%) 129 (25%) 0.31 Summed difference score 0 (0 2) 0 (0 2) 0 (0 2) 0 (0 1) Transient cavity dilation 31 (6%) 28 (5%) 26 (5%) 16 (3%) 0.15 Ejection fraction (%) Rest HR (beats/min) Peak HR (beats/min) minute HR recovery (beats/min) Data are expressed as median (interquartile range), number (percentage), or mean SD. NA not applicable. (multiple imputation) package version for multivariate models only. Continuous variables are expressed as mean SD or as median (interquartile range) for non-normal distributions. They were compared between groups using Student s t tests (or Wilcoxon s rank-sum tests for non-normal distributions) and among groups using analysis of variance (or Kruskal-Wallis tests for non-normal distributions). Continuous variables were visually examined using Q-Q plots to identify significant deviations from a normal distribution. Frequency variables are expressed as number (percentage) and were compared using chi-square or Fisher s exact test. Kaplan-Meier curves and the log-rank test examined all-cause survival by quartile of HR recovery. All applicable tests were 2 tailed, and p values 0.05 were considered statistically significant. Univariate Cox proportional-hazards models explored all variables for subsequent multivariate model building (see list in Table 1). Schoenfeld residuals tested the assumption of proportional hazards and found no significant deviations. Plots of coefficients from univariate Cox proportional-hazards models were visually examined by quartile of each continuous variable for departures from linearity. Two variables, body mass index and HR at rest, appeared visually to have a J- shaped effect. Rest HR showed significant improvement in a nested Cox model after adding its squared term (change in chi-square 4.25, p 0.039), while body mass index did not (change in chi-square 0.59, p 0.44). The 2 variables were treated with simultaneous linear and second-order terms in all models. Plots of coefficients fit a linear regression to a log-transformed version of the equation hazard ratio and its confidence limits A exp(k variable), where A and k are constants, and added a linear offset to align the hazard ratio to unity for the reference quartile. Nested multivariate Cox proportional-hazards models included all variables apart from peak HR and late HR recovery for the baseline model. An incremental, nested Cox model added 5-minute HR recovery. The nested Cox proportional-hazards model provides a baseline chi-square value and a new chi-square value after adding a variable. Change in chi-square for the added variable (1 degree of freedom for late HR recovery) was compared using the chi-square distribution, which is 1 tailed. Results From August 1998 to December 2003, our nuclear cardiology laboratory performed 12,780 stress SPECT studies. Of these, 6,768 (53%) used treadmill exercise stress. The application of inclusion and exclusion criteria limited the final cohort to 2,082 patients, which represented 31% of all treadmill exercise studies during this period. Table 1 lists cohort characteristics and the univariate predictors of survival. During the mean follow-up period of years, typical risk factors were significant univariate predictors of survival. A

4 48 The American Journal of Cardiology ( cutoff of 13% produced an optimal binary variable of late HR recovery for predicting survival (univariate hazard ratio 2.26, 95% confidence interval 1.49 to 3.44, p 0.001). Table 2 lists cohort characteristics by quartile of late HR recovery. Patients with lower late HR recovery were older, more likely to be women, and had a higher incidence of diabetes. Interestingly, they also had higher rest HRs, lower peak exercise HRs, and higher 1-minute HR recovery. Figure 1 shows Kaplan-Meier survival curves by quartile of 5-minute HR recovery, demonstrating worse survival in the lower quartiles. Figure 2 shows the univariate hazard ratio for all-cause mortality for each quartile compared to the one with the greatest recovery, decreasing across quartiles of increasing late HR recovery. Table 3 lists only the significant variables in the baseline and nested multivariate Cox proportional-hazards models. In the baseline model, 1-minute HR recovery was a borderline predictor of survival. Adding late HR recovery improved the baseline model significantly. Importantly, incorporating late HR recovery in the model improved the prognostic significance of 1-minute HR recovery. Late HR recovery also remained a strong predictor of outcome. Figure 1. Kaplan-Meier curves by 5-minute HR recovery. All-cause survival differs among quartiles of late, 5-minute HR recovery, defined as the percentage of the cycle length change between rest and peak exercise that had been recovered after 5 minutes: [1 (RR 5min RR rest )/(RR rest RR peak )] 100. The lowest quartile had the worst survival, corresponding to the group with impaired late HR recovery. Q quartile. Figure 2. Estimates of hazard ratio by late HR recovery. Circles represent the univariate hazard ratio for all-cause mortality for each quartile compared to the one with the greatest recovery (fourth quartile). Solid horizontal and vertical bars represent the interquartile range and 95% confidence interval, respectively. Solid and dashed lines represent the best fit and its 95% confidence interval. Discussion In this study, we evaluated the prognostic significance of late HR recovery. A simple parameter of late, 5-minute HR recovery after treadmill exercise improved the prediction of all-cause survival even after adjusting for covariates including standard early, 1-minute HR recovery. Impaired 5-minute HR recovery was associated with increased mortality. The importance of both components as predictors of outcome likely reflects the different pathophysiologic bases for early and late HR recovery. Thus, our results are the first to identify that the easily obtained parameter of late (5-minute) HR recovery is a novel prognostic index derivable from exercise testing with a substantial impact on survival. One-minute HR recovery first emerged as an important predictor of survival more than a decade ago. 2 This parameter has also been linked to an increased risk for sudden cardiac death. 5 One-minute HR recovery predominantly reflects early parasympathetic reactivation after exercise, with greater HR recovery indicating greater parasympathetic reactivation. In many settings, enhanced parasympathetic effects have been associated with improved survival. We have shown that parasympathetic effects reach a peak approximately 2 minutes into recovery from exercise; sympathetic effects dissipate more slowly, with significant increases in plasma catecholamines and HR even 45 minutes after moderate exercise in controls and subjects with coronary artery disease. 14 Thus, beyond the early minute(s) of recovery, it is likely that the HR response is reflective of sympathetic effects. Late HR recovery therefore provides an index of relief from the sympathetic drive of exercise, with lower values indicating more persistent sympathoexcitation. It is interesting that these processes appear independent with no correlation between early and late HR recovery as defined in this study. Given that late HR recovery is an index of persistent sympathetic tone, it is not surprising that it is also predictive of outcome, as many studies have supported an association between sympathoexcitation and poorer survival. Limited previous research has examined the added prognostic value of late HR recovery. Much of the largest body of research has focused on early HR recovery, either 1 minute 2 or 2 minutes. 3 Limited and very specialized data on 3-minute HR recovery can be found. 15 It is not clear if 3 minutes constitutes early or late HR recovery, and it may be intermediate. As noted earlier, defining HR recovery at later

5 Coronary Artery Disease/Late Heart Rate Recovery 49 Table 3 Nested multivariate Cox models adding late heart rate recovery variable Variable Baseline Model Added Late HR Recovery p Value p Value Age (per 10 years) 1.57 ( ) ( ) Diabetes mellitus 1.87 ( ) ( ) Previous mechanical revascularization 1.49 ( ) ( ) blockers 1.44 ( ) ( ) 0.07 Exercise time (per minute) 0.92 ( ) ( ) Ejection fraction 0.97 ( ) ( ) minute HR recovery (per 10 beats/min) 0.89 ( ) ( ) 0.06 Late HR recovery (per 1%) NA 0.58 ( ) CI confidence interval; NA not applicable. time periods in the same manner as 1-minute HR recovery obscures the possibility of finding a different effect, as 1-minute HR recovery will remain the largest component. A study of 1,400 patients using adenosine stress with supplemental arm exercise instead of treadmill exercise found that abnormal 5-minute HR recovery was a strong, adjusted predictor of all-cause survival after accounting for 1-minute HR recovery. 10 Two studies of apparently the same cohort of 2,000 male veterans examined the prognostic value of 1-, 2-, 3-, and 5-minute HR recovery after treadmill stress in a population referred for evaluation of chest pain. 8,9 The original study found that the 2-minute HR recovery performed better than 1-, 3-, or 5-minute HR recovery for predicting mortality. 8 However, only 1 time point was selected for further model building, and as defined, there is a strong relation among these parameters. In contrast, the present study specifically defined a parameter of late HR recovery so that we could explore simultaneous inclusion of early and late HR recovery parameters. Therefore, it is unknown if their data would support or refute the prognostic value of late HR recovery. A follow-up study examining subgroups with or without heart failure, cardiomyopathy, or -blocker use found that, in a multivariate model, only 2-minute HR recovery was retained when including other clinical variables. 9 There are other potential explanations for the lack of prognostic significance of late HR recovery in this study 9 in addition to the mathematical differences in defining late HR recovery noted previously. The all-male composition of their cohort and rates of heart failure (5%) and cardiomyopathy (16% with ejection fractions 50%) differ from our population. These may explain why their forward-selection model-building approach did not incorporate early and late HR recovery variables. Alternatively, 2-minute HR recovery may itself be a middle ground between early (1-minute) and late (5-minute) HR recovery. Several limitations of our study should be noted. First, all-cause mortality does not distinguish mechanisms of death. Abnormal HR recovery is assumed to reflect underlying abnormal autonomic function, which may manifest clinically by sudden cardiac death, although our data could not test this association directly. Accurately ascertaining if a death was due to sudden cardiac death requires the use of multiple sources of data instead of simply using death certificate reports Falcone C, Buzzi MP, Klersy C, Schwartz PJ. Rapid heart rate increase at onset of exercise predicts adverse cardiac events in patients with coronary artery disease. Circulation 2005;112: Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heartrate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999;341: Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. 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