Background: Abnormal heart-rate recovery (HRR) after exercise testing (ET) is an independent predictor of cardiac mortality.
The aim of this study is to evaluate HRR after ET as an index of the severity of myocardial ischemia in diabetic patients using myocardial perfusion SPECT (MPS)
METHODS: 200 consecutive patients; 40 were diabetics, age 58.8±9.7 yrs referred for MPS using standard Bruce ET protocol. The reduction in heart rate (HR) from its value at peak exercise to the rate 1 min after cessation of stress was determined as the HRR; 21 beats/ min. is defined as the lowest normal value. MPS images were analyzed using 20-segment 5-point scale and summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were calculated.
RESULTS: 24 patients (60%) had an abnormal HRR. These were older 61±9 vs 54±8 (p=0.016), with higher resting heart rate 78±11 versus 91±7 (p=0.001), shorter exercise duration 5.8±1.7 versus 3.6±1.8 (p=0.002) and less METs achieved 5.7±1.2 versus 3.8±1.6 (=0.002) and higher frequency of ECG changes 2 (13%) versus 10 (42%), p=0.017. They had higher SSS 6.2±6 versus 16.6±4.2 (p=0.001), higher SRS 0.9±2.5 versus 7.9±5.6 (p=<0.001) and higher SDS 5.3±5.3 versus 8.7±4.9 (p=<0.002)
Significant negative correlation (r=0.6, P 0.001) was found between HRR and SSS values and between HRR and SRS (r=0.4, p=0.006).
Conclusion, There is a considerable correlation between myocardial ischemia, and the HRR value in patients with diabetes. It seems that the HRR seems to be a reliable marker of the severity of myocardial ischemia.
- CVD= cardiovascular disease
- ETT= exercise treadmill test
- HR= hear rate
- HRR= heart rate recovery
- MPS= myocardial perfusion SPECT
- SPECT = Single Photon Emission Computed Tomography
- SDS= summed difference score
- SRS summed rest score
- SSS= summed stress score
The prevalence of diabetes in world in general (1) and in Egypt in specific has reached epidemic proportions(2) Cardiovascular disease (CVD) is the major cause of death in diabetic patients and is far more prevalent than in the non-diabetic population. One of the non invasive tools to detect coronary artery disease is exercise stress test. The immediate response of the cardiovascular system to exercise is an increase in heart rate due to a decrease in vagal tone. This increase is followed by an increase in sympathetic outflow to the heart and systemic blood vessels.
Heart Rate Recovery
The heart rate (HR) response during exercise and its prognostic implications are well documented (3,4) . The decline in HR after exercise has only recently gained attention. (4-6) . The rise in heart rate during exercise is considered to be due to the combination of parasympathetic withdrawal and sympathetic activation. The decline in HR after exercise has been proposed predominantly to be a function of the reactivation of the parasympathetic nervous system and an abnormal HR recovery after exercise has been found to be a marker of impaired parasympathetic reactivation.
The observations of Imai et al (7) first prompted the clinical evaluation of heart rate recovery. In healthy subjects, athletes, and patients with heart failure, they demonstrated that early (within 1 minute) heart rate recovery was principally the result of vagal reactivation. The phenomenon was abolished by atropine, unaffected by -blockers, independent of workload or age, blunted with heart failure, and accelerated in athletes
Several investigators have established that chronotropic incompetence during exercise and an abnormal heart rate (HR) response after exercise are associated with increased long term mortality (4-6,8) . The relationship persists even after adjustment for atherosclerotic risk factors, exercise-induced ischemic ST-segment depression, and Duke treadmill score.
In normal subjects during progressive treadmill exercise, cardiac output is increased through an augmentation in HR and stroke volume. The increased HR response is mediated in part by withdrawal of vagal tone, increased sympathetic tone, and circulating catecholamines. Immediately after exercise vagal tone is restored, and the HR usually returns to baseline within minutes. However, in some patients, the autonomic balance that governs the HR response during or after exercise is disturbed, resulting in an inability to use most of the HR reserve during exercise (chronotropic incompetence) or an inability to promptly slow the HR immediately after exercise (abnormal HRR). (9).
Abnormal Heart Rate Recovery
An impaired heart rate response on standard exercise testing is related to the risk of an adverse outcome after adjusting for age, ST-segment response, physical activity, and traditional coronary disease risk factors including diabetes, smoking, hypertension, antihypertensive therapy, and the ratio of total to HDL cholesterol. An impaired heart rate response is associated with higher total mortality and with increased risk of coronary heart disease. (10). A blunted heart rate response is associated with late incident coronary heart disease events (events occurring at least 2 years after the treadmill test). (10)
A previous research has shown strong association between mortality and impaired HRR in adults referred for symptom-limited exercise testing and MPS for diagnostic purposes. (4) Another study has shown that HRR measured even as long as 5min following maximal exercise was independently associated with higher CVD and all-cause mortality in men with diabetes. This association persisted even after accounting for age, cardiorespiratory fitness, prior CVD, and other possible confounders. (11)
The aim of our study was to evaluate heart rate recovery after treadmill testing as an index of the severity of myocardial ischemia in diabetic patients diagnosed as having heart disease by Thallium 201 SPECT myocardial perfusion SPECT (MPS).
SUBJECTS AND METHODS:
The study was carried out on 200 consecutive patients with known or suspected coronary artery disease referred to Alexandria University Hospital for exercise stress-rest MPS of these 40 diabetic patients, these comprised our patient population. Informed consent was taken from every patient included in the research.
Patients with any of the following were excluded: congestive heart failure, Previous myocardial infarction, Congenital or valvular heart disease, Cardiomyopathy, arrhythmias, or inability to perform treadmill testing.
Exercise myocardial perfusion SPECT
After 5 minutes of supine rest, a 3-lead electrocardiogram (ECG) was obtained at baseline for 1minute. Exercise treadmill testing (ETT) using standard Bruce protocol was performed with continuous in all subjects. At peak exercise, thallium-201 3-3.5 mci was injected intravenously and the patient continued to exercise at the same workload for an additional 1 minute. Blood pressure and cardiac status were monitored using 3-leads ECG and recorded during the exercise and at 1-minute intervals for 5 minutes after exercise. Exercise was terminated if there was increasing chest pain, a decrease in blood pressure >20 mmHg, limiting dyspnea or fatigue or sustained arrhythmia. Heart rate recovery (HRR) was obtained by subtracting heart rate at the first minute of recovery from peak heart rate obtained during exercise. Abnormal HRR was defined as HRR?21 beats per minute (12).
Chronotropic response was defined as the percentage of maximal age-predicted heart rate achieved at peak exercise: peak heart rate divided by ( 220-Age); a value of 85% or greater is considered to be normal. Heart-rate reserve (%) was calculated by the following equation: Rate peak-Rate rest divided by (220-Age) -Rate rest X100. (13)
Within 5 min of thallium injection, SPECT images were acquired using a single -head camera (Siemens Orbiter) with a high-resolution collimator rotated in a 180o orbit. Three hours later, delayed images were obtained. Images were interpreted by 1 experienced observer. Semi- quantitative visual interpretation of myocardial perfusion SPECT was performed with short-axis and vertical long-axis tomograms, which were divided 20 segments (14) . Each segment was scored using a 5-point grading system (0=normal to 4=absent). The summed stress (SSS) and the summed rest scores (SRS) were obtained respectively. The difference between the SSS and the SRS was defined as the summed difference score (SDS), a marker of inducible ischemia, A SDS >2 indicated presence of ischemia.
ECG was considered ischemic if a horizontal or downsloping ST-segment depression > 1and 0.5mm respectively measured 80 milliseconds after the J-point as compared with rest ECG.
Results were analyzed suing commercially available SPSS 15.0 A probability value of <0.05 was considered statistically significant.
Continuous variables are listed as mean ± SD. Comparisons between patients normal HRR and those with abnormal HRR were performed with the Chi -square test for categorical variables and the students t-test for continuous variables. The correlation between various MPS scores and HRR were derived by Pearson correlation analysis.
Our study comprised 200 patients referred for exercise-rest MPS of these 40 were diabetics with no other cause of impaired heart rate recovery. Mean age was 58.8±9.7 years; 30 patients (75%) were males, 22 patients (55%) had hypertension. 19 patients (47.5%) were smokers. They exercised for an average of 4.5 ±2.2 minutes and average METs achieved were 4.6± 1.7. The mean value of HRR was 24±12.7 beats/min (range 7 - 56 beats/min). Most of the patients (32, 80%) had an abnormal MPS. Mean SSS SRS and SDS are 12.4 ±7.0, 5.0±5.7, and 7.4±5.3 respectively
Twenty four patients (60%) had an abnormal HRR value (= 21 beats/min). Baseline clinical characteristics of the 2 groups are outlined in Table 1.
Difference in exercise stress test parameters and MPS results of the 2 groups is demonstrated in Table 2. Patients with normal HRR (group I) value had a lower resting heart rate and a significantly better performance during exercise testing (greater exercise duration, better chronotropic response, higher heart rate reserve, higher values of maximal heart rate, maximal systolic blood pressure, double product, and METs at peak exercise workload ) (Table 4). On the other hand, patients with abnormal HRR (Group II) were more frequently reported angina during exercise had a positive ECG and an abnormal chronotropic response. Considering chronotropic variables, patients with abnormal HRR had less peak heart rate, more abnormal chronotropic response (unable to reach 85% of target heart rate); 54% versus 12.5% (p=0.0023) and less mean heart rate reserve (%); 63 ±15 versus 87±14 (p=0.0001) than patients with normal HRR
Lastly, MPS showed severe myocardial ischemia they had higher SSS, SRS and SDS. Fig 1 summarizes the myocardial perfusion results as a function of heart rate recovery
The correlation results between MPS scores and HRR and HR reserve are shown in Table 3 and 4. A significant negative correlation (r=0.6, P0.001) was found between the values of HRR (1 min after the end of the exercise) and SSS values and also between HRR and SRS ( r=0.4, p=0.006). A non-significant association was found between HRR and SDS (r=0.15, p=o.3). Fig 2 and 3 respectively.
HRR after exercise is a well-validated independent predictor of cardiovascular and all-cause mortality. (5,6) on the other hand, there are only few data on the association of myocardial ischemia with HRR, especially in diabetic patients, This study sought to evaluate HRR after ET as an index of the severity of myocardial ischemia in diabetic patients using Thallium-201 MPS,.
Previous studies including a general cohort of patients, have already reported the relationship between exercise heart-rate response and myocardial perfusion and between myocardial ischemia and HRR. In particular, they found a significantly higher frequency of the presence of myocardial perfusion defects among patients who failed to achieve at least 85% of the age predicted maximum heart-rate or who had a low chronotropic index, while we have reported a significant association between HRR and myocardial perfusion imaging. (12,15)
This may be attributed to the fact that in the current study, we excluded patients whose HRR might have been affected by factors other than myocardial ischemia. Therefore, we believe that the significant correlation between the HRR and the MPS scores indicates the influence of ischemia on its value.
Conversely, Desai et al concluded in their study that patients with an abnormal HR recovery do not appear to have an increased incidence or more severe myocardial infarction or ischemia (16). This is most probably attributed to patient cohort; where in the latter study they did not exclude patients with a history of myocardial infarction (the implication of myocardial infarction to innervation of myocardium is well known)
Furthermore, Lima et al. in a recent publication did not find an independent association between SSS and HRR (HRR was significantly correlated only with age, heart rate at rest, exercise duration and chronotropic incompetence) (17) . Significant differences in methodology and in particular in patient selection (inclusion of patients with a prior myocardial infarction or a previous cardiac surgery, exclusion of patients using beta blockers or calcium channel antagonists commonly used in patients with myocardial ischemia) could explain, at least partially, the different results.
In our study, patients with normal HRR had less frequent incidence of chest pain on ETT, positive ECG changes and better MPS results as compared with the subgroup with an abnormal heart rate recovery value.; these results are in concordance with published literature (4-6) .
Patients with a normal value of heart rate recovery had significantly better myocardial perfusion (as estimated by the myocardial perfusion SSS. Cole et al (4)(59) also reported a higher proportion of patients with perfusion defects on MPS in the group with pathologic heart rate recovery, whereas Desai et al (83) did not find a statistically significant difference (16).
The relationship we found between the HRR and the chronotropic variables (peak heart-rate, chronotropic response, heart-rate reserve) is comparable with the results of previous studies which showed HRR as a predictor of mortality (5,6).
The results of our study are generally in concordance with the results of Cheng et al. in a cohort study of men with diabetes, who suggested that patients with impaired HRR (defined as the heart rate decline during the first 5 min after the completion of the maximal exercise test) had a higher risk of cardiovascular disease (11).
HRR AND THE AUTONOMIC NERVOUS SYSTEM:
Cardiac acceleration during exercise and deceleration after exercise is thought to involve an interplay between the two limbs of autonomic nervous system; sympathetic and parasympathetic nervous system. There is evidence pointing towards the possibility of accentuated antagonism, (the activity of one limb of the autonomic nervous system is directly related to the activity of the other), i.e. the higher the chronotropic response, the more the HR recovery and vice versa. (15)
EFFECT OF DM ON HRR:
Attenuated HRR following maximal exercise test is a predictor of mortality in healthy adults and in those referred for diagnostic testing (4). These findings are independent of workload achieved during the test, presence or absence of myocardial perfusion defects, and changes in heart rate during the exercise test. Panzer et al. recently reported that fasting plasma glucose is strongly and independently associated with abnormal HRR, even at nondiabetic levels (18).
In one study, men with diabetes who had slow HRR at 5 min following a maximal exercise test had a higher risk of CVD and all-cause mortality when compared with similar men who had more rapid HRR. The high risk in men with slow HRR persisted after adjustment for cardiorespiratory fitness, baseline prevalence of CVD, and other potential confounding variables (11).
It is important to note, however, that HRR was not the strongest predictor of risk. Therefore, when assessing risk in men with diabetes it should not be used alone but rather in conjunction with other strong predictors, such as cardiorespiratory fitness theorized to be due to high vagal tone associated with fitness and good health.) .(11)
Epidemiological studies have consistently shown that low physical activity and low cardiorespiratory fitness are associated with high rates of cardiovascular and total mortality. Data also suggest that low physical activity or low cardiorespiratory fitness leads to a higher incidence of type 2 diabetes and nonfatal CVD (19). This may be due to a number of unfavorable biochemical and physiological alterations associated with inactivity (19,20). Low cardiorespiratory fitness is also strongly associated with increased mortality risk in men with type 2 diabetes (21). The strong association between faster rates of HRR and the greater percentage of fit men in the high HRR group suggest that higher levels of fitness, presumably derived from exercise training, may positively affect autonomic function in men with diabetes. Thus ,the exercise test, which is simple, safe, and inexpensive, can be used as a powerful tool for clinical risk stratification in diabetic men by noting both HRR and cardiorespiratory fitness(21).
HRR AND CHRONOTROPIC INCOMPETENCE:
In previous studies, the association of autonomic dysfunction with diabetes has been evaluated by heart rate variability (22),
It is well documented that chronotropic incompetence (defined as an inability to achieve 85% of age-predicted heart rate) and impaired HR reserve % are independent predictors of increased mortality (15). In our present study, we found a striking correlation between the chronotropic markers of exercise testing (peak HR, peak HR%, duration of exercise and HR reserve %) and HR recovery at 1 min after exercise. Mean values of these chronotropic variables were also significantly lower in patients with an abnormal HR recovery.
Effect of HRR on Mortality In Relation To Coronary Angiography:
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. (23) The association between abnormal HRR and mortality was examined among men and women referred for exercise stress testing and coronary angiography. 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. In fact, abnormal HRR provided additive prognostic information to the angiographic severity of CAD. (23) A score including HR recovery, METs, age and history of typical angina pectoris was superior to cardiac catheterization data for predicting prognosis. To date, this measurement has not been evaluated as a diagnostic indicator, and was not diagnostic of angiographic CAD.
Prognostic value of heart rate reserve:
Failure to reach 85% of the age-predicted maximum HR is independently predictor of death but failure to use 80% of HR reserve is a substantially stronger predictor of risk (24). Azarbal et al. concluded that chronotropic response predicts outcome over and above functional capacity and that combining chronotropic response with functional capacity would identify patients who are at very low risk (24).
Our study underscores the values of exercise stress data in patients undergoing MPS study; it has a clear diagnostic value and HRR may be considered a marker of myocardial ischemia. The clinical implications of these findings are: First, the HRR and HR reserve approach should be used and may replace the traditional percent of age-predicted HR achieved. Second exercise nuclear studies that show chronotropic incompetence and normal myocardial perfusion imaging should not be considered non-diagnostic or sub maximal as these patients are probably at high risk and need further testing. Thus, patients referred for nuclear imaging should be specifically referred for treadmill stress if they are capable of exercise (25)
Abnormal HRR on exercise treadmill testing was associated with a high prevalence of abnormal and high-risk stress MPI findings, even in patients without other exercise treadmill testing findings that traditionally would prompt further testing. These findings suggest that further testing with stress MPI should be considered in patients with abnormal HRR on routine exercise treadmill testing.(26)
Heart rate recovery is a readily obtainable, relatively inexpensive and very simple diagnostic and prognostic tool which clinicians can employ in clinical patient management. In the present study abnormal HRR was significantly associated with greater perfusion defect extent and severity at stress and rest Therefore, abnormal HRR may reflect myocardial damage.
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