CHACKO, KAREN M.1; BAUER, TIMOTHY A.1,2; DALE, RITA A.2; DIXON, JAMES A.1; SCHRIER, ROBERT W.1,2; ESTACIO, RAYMOND O.1,2
Cardiovascular (CV) disease is the leading cause of death among patients with type 2 diabetes mellitus (T2DM) (16). Traditional risk factors, including hypertension, smoking, and cholesterol, as well as nontraditional risk factors such as microalbuminuria, left ventricular mass, and abnormal autonomic function (5,20,26), have been identified as predictors of future coronary events and death among this population of patients. However, one major limitation of available risk factors is the reliance on clinical information that occurs relatively late in the T2DM disease process (33). Thus, the identification of a prognostic marker that occurs earlier in the disease process of T2DM could lead to improved treatment guidelines and outcomes in this growing patient population.
Heart rate recovery (HRR) has emerged as a novel marker for mortality in predominantly nondiabetic populations (6,7,22,36) and has been associated with the occurrence of CV events in other patient groups (27,32). An attenuated HRR immediately after exercise is considered an index of autonomic imbalance and may identify clinically silent autonomic dysfunction. Because autonomic dysfunction is a common complication in patients with T2DM that can be reversed with strict glycemic control (39), it may be useful to identify those patients at risk as early as possible. However, the relationship of HRR and cardiac-related events in patients with diabetes mellitus remains to be clarified, and is particularly relevant because patients with T2DM may be increasingly referred for screening exercise treadmill testing on the basis of the American College of Cardiology/American Heart Association guidelines (18).
The purpose of this study was to evaluate the relationship of 1- and 2-min HRR and the incidence of all-cause and CV mortality, and CV events in patients with T2DM who had exercise treadmill testing performed on a screening basis. We hypothesized that subjects with attenuated HRR (1 and 2 min after exercise) would be at increased risk of CV mortality and CV events. The study was performed on a cohort of T2DM patients from the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (14).
Study design and participants.
Exercise data were abstracted retrospectively from chart review from baseline exercise treadmill tests in patients enrolled in the ABCD trial (1991-1993). The ABCD trial was approved by the Colorado multiple institutional review board, and written informed consent was obtained from all study subjects before their participation. Study design, protocol, and results for the ABCD trial have been previously described (13,14). Briefly, the ABCD trial was a large, single-site, prospective, randomized, blinded trial designed to measure the effects of moderate versus intensive blood pressure control, using initial therapy with an angiotensin-converting enzyme inhibitor (ACEI), enalapril, or a calcium channel blocker, nisoldipine, on renal and cardiovascular outcomes in patients with T2DM. On entry, asymptomatic patients with T2DM were enrolled if they had a diastolic blood pressure of at least 80 mm Hg and were not on antihypertensive medications. Patients were primarily recruited from a major metropolitan area. Exclusion criteria included unstable angina, myocardial infarction or cerebrovascular accident (CVA) within 6 months of entry, coronary artery bypass grafting (CABG) surgery within 3 months of entry, New York Heart Association class III or IV heart failure, severe peripheral vascular disease, isolated systolic hypertension (systolic blood pressure > 160 and diastolic blood pressure > 90 mm Hg without or before medical therapy), serum creatinine greater than 3 mg·dL−1 (265 μM·L−1), and patients who had an absolute need to be on an ACEI or calcium channel blocker for therapy. During a placebo run-in period, all baseline studies, including exercise testing, were performed. Patients underwent renal, retinal, and neural assessments frequently throughout the trial, as has been previously described. (14)
Of the 950 participants enrolled in the ABCD trial, 890 underwent exercise treadmill testing at baseline before randomization of drug therapy. The remaining 60 patients were either unable to physically perform exercise testing or refused testing. All exercise tests were performed after a 7- to 11-wk washout period from any antihypertensive medications. This included beta-adrenergic-blocking medications. Digoxin therapy was deemed essential and, therefore, was continued in 77 (8.7%) patients during the washout period and was present in these patients during exercise testing.
Exercise testing was performed at a single site, using a modified Bruce protocol (2). During each stage of exercise, data on symptoms, heart rate, blood pressure, and ECG changes were recorded. Patients were encouraged to reach symptom-limited peak exercise using the Borg scale to help objectively assess when a patient had attained maximal exertion (3). The recovery period consisted of 2 min of walking at 1.9 km (1.2 miles) per hour on a 0% grade. Heart rate was recorded every minute for up to 5 min during the recovery period. Heart rate data was obtained from ECG printouts of 10-s averaged heart rate data collected at exactly 1 and 2 min into recovery for each subject, for entry into the database.
Definition of HRR and chronotropic incompetence.
HRR was defined as the value between the heart rate at peak exercise (immediately before termination of the test) minus the value at either 1 or 2 min into the recovery period (1-min HRR and 2-min HRR). Chronotropic incompetence (CI) was defined as the inability to reach 85% of predicted maximal heart rate (2). Predicted maximal heart rate was calculated as 220 − age in years.
The ABCD subjects were followed for 5 yr after the last patient enrollment. Enrollment lasted for 2 yr, so subjects had the opportunity for 5-7 yr of follow-up, depending on when they were enrolled. Time to event for survival analysis was calculated as the time from randomization to either event or the patient's last follow-up day without an event. An independent end point committee blinded to the study arms adjudicated all CV events. Cardiovascular mortality included death from progressive congestive heart failure (CHF), fatal myocardial infarction, fatal arrhythmias, CVA, ruptured aortic aneurysm, and sudden death. Cardiovascular events included all categories of CV mortality plus nonfatal myocardial infarction, nonfatal CVA events, and CHF requiring hospital admission. Evidence of macrovascular complications was defined as patients with an ankle:brachial index < 0.9 or a history of cardiovascular disease. Microvascular disease includes patients with neuropathy, retinopathy, or overt albuminuria at baseline.
SAS software version 8.2 or higher (SAS Institute, Cary, NC) was used for all statistical analyses. Two-sided P values of less than or equal to 0.05 were considered significant. The study population included the 890 patients with exercise test data at baseline of the ABCD trial. Baseline characteristics were compared between those with HRR at 1 min of less than or equal to 12 bpm and those greater than 12 bpm. Categorical variables such as race were compared using a chi-square test. Continuous variables such as age were compared using Student's t-test.
Initially, the relationship of CV events and mortality was explored using the published abnormal HRR cutoff at 1 min of < 12 bpm (6). To further explore our specific T2DM population, HRR values at 1 and 2 min were divided into quintiles, and their independent associations with all-cause and CV mortality and CV events were assessed with a chi-square test. Multiple-comparisons-adjusted Fisher's exact P values were employed to contrast event rates among combinations of pairwise comparisons among the five quintiles.
Kaplan-Meier (24) estimates were used to plot the survivor curves for time to event stratified by HRR quintiles. The survival curves were compared using the log-rank test. Six Cox regression models (1) were fit to examine the relationship of all-cause and CV mortality and CV events with quintiles of 1- and 2-min HRR, adjusting for other suspected risk factors. To compare the magnitude of the effect of HRR at 1 and 2 min across the three outcomes, these covariates were consistent in all six models. We included covariates with clinical relevance including age, race, gender, duration of exercise, CI, urinary albumin excretion, evidence of macrovascular complications, total cholesterol, baseline systolic blood pressure, smoking status, duration of diabetes, study drug (either enalapril or nisoldipine), and blood pressure goal (intensive or moderate). Urinary albumin excretion is positively skewed, so the natural log transformation was used in the Cox regression models. Colinearity among the exercise measures included as adjustment factors was tested visually and was deemed insignificant.
Characteristics of the ABCD participants who underwent exercise testing at baseline are shown in Table 1. Patients with an attenuated HRR (< 12 bpm) at 1 min after exercise (N = 188) were older, had longer duration of diabetes, higher seated heart rate, higher systolic blood pressure at entry into the study, and shorter exercise times, and were more likely to have CI compared with those subjects without attenuated HRR after exercise. Those with attenuated HRR were also more likely to have microvascular disease, defined by overt albuminuria, retinopathy, or neuropathy at baseline (P < 0.01). The log transformation of urinary albumin excretion was significantly higher in those with HRR < 12 bpm (P < 0.01), as was the serum creatinine level (P < 0.01). There was no evidence of an association between history of macrovascular disease and attenuated HRR (P = 0.81).
One- and two-minute HRR data according to quintile are presented in Table 2. Data for 1- and 2-min HRR were not available for 19 and 23 of the 890 patients, respectively. The event rates were lowest in the middle quintiles when HRR ranged from 19-28 bpm at 1 min and 37-49 bpm at 2 min. The highest event rates were found in the lowest or most attenuated HRR quintile. All-cause mortality and CV events were significantly greater among the lowest quintile (< 12 bpm) of 1-min HRR compared with the fourth (23-28 bpm) quintile. Similarly, all-cause mortality and CV events were significantly greater among the lowest quintile (< 28 bpm) of 2-min HRR compared with the third quintile (37-42 bpm) quintile. Event rates seemed to increase slightly in the highest or most rapid HRR quintiles for all-cause and CV mortality and CV events. However, after adjustment for multiple comparisons, only the most attenuated quintile of HRR had significantly higher event rates in pairwise comparison with any of the other quintiles. The significant pairwise P values are provided in the legend of Table 2.
The median follow-up time from randomization to either event-free survival time or first cardiovascular event was 5.0 (range 0-6.9) yr. The Kaplan-Meier survival estimates for time to CV event or censoring stratified by quintiles of HRR at 1 min are plotted in Figure 1. The estimated 5-yr survival rates and 95% confidence limit (CL) from lowest (< 12 bpm) to highest quintile (> 28 bpm) were 80% (73-85%), 89% (84-93%), 90% (84-94%), 89% (83-93%), and 86% (79-90%). The log-rank test, used to compare these unadjusted survival curves across the five quintiles, shows a statistically significant difference among the groups (P = 0.007).
FIGURE 1-Kaplan-Meie...Image Tools
Hazard ratios from the Cox proportional hazards regression models testing the time to occurrence of all-cause and CV mortality and CV events for quintiles of HRR are displayed in Tables 3 and 4. The hazard ratio of a CV event was decreased by half for those in middle quintiles of HRR of both 1- and 2-min HRR (hazard ratio = 0.5, 95% CL 0.3-0.8, and hazard ratio = 0.5, 95% CL 0.3-0.8, respectively) compared with the lowest quintiles. When compared with the reference group of < 28 bpm, patients with a 2-min HRR between 37 and 42 bpm had a significantly lower risk of all-cause mortality (hazard ratio = 0.1, 95% CL 0.03-0.5).
The hazard ratio of all-cause mortality was increased for those with CI in the 1-min model (hazard ratio = 1.9, 95% CL = 1.1-3.4). As expected, age was consistently associated with increased risk mortality and events in the models. The unadjusted log-rank statistic comparing survival curves for each quintile were significant for each of the comparisons, with the exception of the model for CV mortality and 1-min HRR, as presented in Tables 3 and 4.
The present study demonstrates that attenuated HRR is associated with an increased risk of all-cause mortality in asymptomatic patients with T2DM. Additionally, an attenuated HRR was also associated with an increased risk for CV events in this population of T2DM patients. Thus, in addition to serving as an important prognostic marker of mortality, the attenuation of HRR may also identify individuals with T2DM at high risk for cardiovascular-related events and highlight those patients who are candidates for therapy directed at attenuated HRR.
Previous studies in predominantly nondiabetic populations referred for treadmill testing have demonstrated that an attenuated 1-min HRR after peak exercise, commonly defined as < 12 bpm, can be used as a prognostic marker for all-cause mortality (6,7,28,36). Furthermore, attenuated HRR has been found to be predictive of all-cause mortality independently of Duke score (7,28) and severity of underlying coronary disease (10,40). The usefulness of prognostic markers from exercise treadmill tests is highlighted by the most recent modification to the American Heart Association guidelines for exercise testing (18), which found that the weight of evidence is in favor of screening exercise testing in patients with diabetes.
To our knowledge, only one study has previously demonstrated an association between attenuated HRR and CV events (32), conducted in a population of patients with familial hypercholesterolemia. Exploration of the Framingham data (27) failed to yield a significant association between HRR and CV events. In the present study of asymptomatic patients with T2DM, these data demonstrate higher CV event rates in those patients that had an attenuated HRR at 1 or 2 min into recovery, consistent with the work by Pitsavos et al. (32).
The potential mechanisms linking abnormal HRR and CV events are unclear. Attenuated HRR is considered to reflect abnormal control of autonomic function, suggesting reduced parasympathetic activity (21), increased sympathetic activity, or both after peak exercise. Low vagal tone and high sympathetic states have both been linked to excess mortality (34), particularly from sudden death, which is believed to be mediated through fatal arrhythmias (23,25). However, unlike the majority of markers for CV events in T2DM that focus on atherosclerotic disease and endothelial dysfunction as the basis of pathophysiology, attenuated HRR would seemingly identify those at risk for sudden death (22), although this relationship has not been rigorously evaluated. In this context, it is interesting to note that fasting plasma glucose, ratio of trigylcerides to high-density lipoproteins, diabetes, endothelial dysfunction, and recently myocardial perfusion have all been associated with an attenuated HRR (17,30,35,37). Thus, it seems that factors associated with the progression of T2DM could provide a pathophysiologic rationale for the association of attenuated HRR with CV events in our study.
Only one other study has specifically examined HRR and outcomes in patients with diabetes. Cheng et al. (4) have demonstrated an association between 5-min HRR and mortality in diabetic men. It seems unlikely that this association at 5 min after exercise can be solely explained on the basis of abnormal vagal tone (21), but it could also describe prolonged sympathetic activation in those patients. Nevertheless, although the decrement of heart rate later in recovery may still be partially attributed to continued vagal reactivation, the slower withdrawal of sympathetic activation could play a larger role in determining heart rate as recovery continues beyond 1 min (31). The present study is the first to specifically examine attenuated HRR in patients with T2DM as it relates to CV outcomes and mortality at 1 and 2 min after exercise, the time points suggested as most relevant to autonomic imbalance.
An intriguing finding in our study was that event rates did not steadily decrease with more rapid HRR. In fact, we observed an increase in event rates among those with the most rapid 1- and 2-min HRR, although the observed increase in events was not significant when adjusted for multiple comparisons. However, we note higher event rates also occurred in patients with more rapid HRR in other published studies (6,22,28). Although it is difficult to speculate on the underlying mechanisms for this observation, altered sympathetic tone or baroreflex sensitivity may explain these observations. Further work is necessary to evaluate the potential relevance and mechanisms of abnormally rapid HRR and the occurrence of CV events.
A significant confounder to the evaluation of HRR in persons with T2DM may be related to CI (8), a factor that may be related to latent autonomic neuropathy in T2DM and can affect measures of fitness. As expected, patients with CI showed little variability with regards to peak exercise heart rate, percent of age-predicted maximum heart rate, and time on treadmill. To control for an abnormal chronotropic response, we included both HRR and CI parameters in our Cox regression models. Both HRR and CI consistently emerged as predictors of CV events and mortality in the presence of other disease risk factors, including urinary albumin excretion.
Other studies have been limited by the influence of patients taking beta-blockers at the time of exercise testing (6,7). However, this was not true for our study population, in which no patients were on beta-blockers at the time of their exercise test. Additionally, because the ABCD trial was originally designed to prospectively test outcomes in a diabetic population without cardiac symptoms at baseline, all exercise tests in these patients were performed as part of a baseline screening characterization, and we were therefore able to avoid the referral bias for exercise testing present in previous studies (6,9,11,24,28). Note that a small percentage of patients in the present study remained on digoxin therapy during exercise testing. Although this can lower resting heart rate, the effects on heart rate during exercise and maximal heart rate are considered negligible (15).
The ABCD trial consisted of a normotensive and a hypertensive cohort, and cohort-specific results have been published previously (12). We adjusted for the study design and intervention by pooling the data from both cohorts and adjusting for baseline systolic blood pressure and study interventions. In addition, our study population was limited to patients who underwent exercise testing at baseline. Sixty patients who did not undergo exercise testing at baseline had higher rates of both all cause and CV mortality than those who did undergo testing at baseline. Thus, although the results of this retrospective study must be qualified, our findings suggest a strong relationship between abnormal HRR and CV events in a diabetic population that may be representative of the population at large.
Our results suggest that both slowed HRR and possibly very rapid HRR at 1 and 2 min should be considered when assessing risk of mortality and CV events in future studies. The usefulness of HRR may go beyond simple prognostic information, as recent work has focused on HRR as a modifiable risk factor. It has been demonstrated that exercise training can improve autonomic dysfunction and, thereby, HRR in this population (19). Another consideration is the use of pharmacological interventions to alter the autonomic balance, similar to what has been done using beta-blockade in patients with heart failure (29) or statins in patients with diabetes (38). Targeting autonomic dysfunction in T2DM with lifestyle and pharmacological interventions may thus be indicated for patients with autonomic dysfunction versus those without autonomic abnormalities. Future studies are needed to address this interesting possibility.
In conclusion, the present study performed in patients with T2DM provides further support for the utility of HRR in gauging risk for future morbidity and mortality in an asymptomatic population. Unique to this study is the finding that HRR can also be used for prognosis in determining CV events. In T2DM, quintiles of 1- and 2-min HRR were found to be independently predictive of CV events after adjusting for other traditional risk factors. The models also confirmed that CI is a strong predictor of all-cause mortality. Thus, HRR and CI provide information beyond the traditional CV risk factors that could aid in the clinical risk stratification of asymptomatic T2DM patients. Our results support prior work that suggests that HRR and CI should be incorporated into standard diagnostic treadmill testing with particular regard to the T2DM population. Therapies directed at normalizing HRR in this high-risk group of patients should be pursued.
The ABCD trial was supported by Bayer Pharmaceutical Company and the National Institute of Diabetes, Digestive, and Kidney Diseases (DK50298-02). Dr. Bauer is supported by NIH F32 DK078413-01. Dr. Dixon was supported by the General Internal Medicine Division's Research Scholars Program for medical students at the University of Colorado at Denver and Health Sciences Center.
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