Abstract
Gulati and colleagues reported heart rate response, chronotropic incompetence (defined as an attenuated heart rate response to exercise) and chronotropic reserve in asymptomatic women submitted to symptom-limited exercise stress testing according to the Bruce protocol [1]. The study population was a cohort of 5437 asymptomatic women aged 35 years or older who volunteered to participate in the St James Women Take Heart Project [2] after a call in Chicago area in 1992 and were followed up for 15.9 ± 2.2 years [1]. In the same project, Gulati and colleagues previously demonstrated that exercise capacity was an independent predictor of death in asymptomatic women (greater than in men) [2] and later published a nomogram for predicted exercise c apacity in men and women [3]. Among the interesting characteristics of this large study population was the fact that participants were asymptomatic women. It has long been believed that the performance of men and women submitted to exercise stress testing is different. The concept has a strong basis in clinical practice. Previous reference values on the performance of exercise stress testing were largely based in study samples with male predominance or symptomatic patients submitted to diagnostic investigation. Furthermore, maximum heart rate has usually been assumed to be 220-(age).
Results
The results of the study demonstrated a linear relationship (p < 0.001) between increasing age and a decrease in peak heart rate achieved with exercise testing (linear regression). The derived equation was: peak heart rate = 206-0.88(age).
This expression is different from the largely adopted traditional expression of 220-(age) as the predicted maximum heart rate. The formula developed in the current study provided new means of estimating failure to reach a target heart rate. According to the traditional expression, 336 (7%) women failed to reach 85% of age-predicted heart rate and according to this new expression, 173 (3%) participants failed. Chronotropic index (ratio of heart rate reserve to the metabolic reserve) was less than 0.8 in 939 (17%) women by the traditional estimate. By contrast, chronotropic index was estimated at less than 0.8 in 496 (9%) using the equation derived in this study.
The authors evaluated chronotropic incompetence by estimating chronotropic index. They found that participants with chronotropic incompetence (chronotropic index < 0.8) were older (55 ± 11 years vs 52 ± 11 years; p < 0.0001), had a higher BMI (29.3 ± 6.7 kg/m2 vs 27 ± 5.6 kg/m2; p = 0.0001), were more frequently smokers (140/496, [28%] vs 695/4941, [14%]; p < 0.0001), had lower HDL-cholesterol (47.1 ± 15.2 mg/dl vs 52.1 ± 14.7 mg/dl; p < 0.0001), were more frequently hypertensive (279/496, [56%] vs 2079/4941, [42%]; p < 0.0001) and had a higher Framingham score index (8 ± 5.6 vs 5.5 ± 5.9; p = 0.0001).
Some variables of exercise stress testing were also different between participants with a chronotropic index of less than 0.8 and 0.8 or more, respectively: heart rate (beats per minute [bpm]) at stage 2 (125 ± 13 bpm vs 145 ± 16 bpm; p < 0.0001), peak heart rate (135 ± 12 bpm vs 162 ± 13 bpm; p < 0.0001), change in heart rate from rest to peak exercise (56 ± 13 bpm vs 84 ± 15 bpm; p < 0.0001), number of participants who reached 85% or higher of age-predicted heart rate (323/496, [65%] vs 4941/4941, [100%]; p < 0.0001), frequency of angina (10/496, [2%] vs 30/4941, [0.6%]; p < 0.0001) and exercise capacity in METs (6.5 ± 2.5 vs 8.2 ± 2.7; p < 0.0001).
Furthermore, the researchers developed a nomogram for asymptomatic women relative to the traditional estimate. Values of 100% peak heart rate for women expressed by 206-0.88(age) were lower than the 100% peak heart rate for men expressed by 220-(age).
The significant hazard ratios of all-cause mortality in multivariate analysis were: stage 2 heart rate: 0.97 (95% CI: 0.97–0.98; p < 0.001); peak heart rate: 0.98 (95% CI: 0.97–0.99; p < 0.001); heart rate increase to reach peak heart rate value: 0.98 (95% CI: 0.97–0.99; p < 0.001); 1 standard deviation or more below mean peak heart rate: 1.84 (95% CI: 1.52–2.21; p < 0.001); and chronotropic index, estimated with the heart rate values estimates by the expression derived in the current study, 206-0.88(age): 1.3 (95% CI: 1.03–1.63; p = 0.023). Interestingly, chronotropic index estimated by age-predicted heart rate made by the traditional definition, 220-(age), was included in the multivariate modeling and was not significantly associated with all-cause mortality.
The comparison of the best model between chronotropic index and all-cause mortality revealed that the model with the chronotropic index defined in this study was better than the chronotropic index defined according to the traditional estimate for age-predicted heart rate. The new formula identified fewer women as chronotropically incompetent and was a more accurate predictor of all-cause mortality.
Significance
The findings of the study support the hypothesis that maximum heart rate relative to age based on studies with a predominance of male patients may be an overestimate for women and demonstrated an inverse relationship between peak heart rate with increasing age. Previously, we have observed that an inverse relationship of maximum daily heart rate with increasing age was also apparent in individuals with no evidence of heart disease on common everyday living activities evaluated by 24-h ECG monitoring [4].
Chronotropic incompetence as estimated by the expression derived in this study made the statistical modeling a better fit to evaluate the association with all-cause mortality. Interestingly, our observation of a smaller sample of asymptomatic women with no evidence of heart disease after clinical and laboratory examination submitted to exercise stress testing did not demonstrate a significant difference in peak heart rate reached during exercise by women relative to men [5]. Furthermore, vascular function evaluated by forearm blood flow in asymptomatic individuals without any evidence of heart disease submitted to isometric exercise (e.g., handgrip) was lower in women and decreased as BMI increased [6].
The authors discussed the chronotropic incompetence as a surrogate of underlying autonomic dysfunction not necessarily related with myocardial ischemia. Previously, we have observed that heart rate variability in asymptomatic individuals without any evidence of heart disease revealed differences relative to age and gender: variability decreased significantly until the fourth decade of life and decreased nonsignificantly thereafter in older age groups; indexes of parasympathetic modulation (i.e., HF, rMSSD, pNN50) were higher in women [7]. Heart rate recovery after exercise, is considered to be a function of reactivation of the parasympathetic drive and a decrease in the sympathetic drive. Heart rate recovery after exercise demonstrated a statistically significant correlation with age: younger individuals recovered faster than older ones from the second to the fifth minute after exercise (r = 0.19–0.35; p < 0.05). Heart rate recovery in women was more rapid than in men: after exercise the rate was 4 ± 1.1 (<0.05) beats more rapid at the first minute; 5.7 ± 1.2 (p < 0.05) beats more rapid at the second minute; and 4.1 ± 1.1 (p < 0.05) beats more rapid than in men at the third minute. We found no association between heart rate recovery and heart rate variability for the first and second minutes of recovery after exercise, neither in time nor in frequency domains [8].
Executive summary
Peak heart rate during exercise in asymptomatic women demonstrated an inverse relationship with increasing age, expressed by 206-0.88(age), which was lower than the traditional estimate of 220-(age).
Chronotropic incompetence in asymptomatic women was independently associated with an increased risk of all-cause mortality.
Chronotropic incompetence estimated with the new formula 206-0.88(age) derived in this investigation was a more accurate predictor of all-cause mortality in comparison to the traditional estimate 220-(age).
Future perspective
Further studies may evaluate heart rate response to exercise and chronotropic incompetence in other samples of women with different genetics, ethnicity, lifestyle and BMI to confirm the findings of this study. In the event of confirmation of the findings, maximum heart rate for women submitted to electrocardiographic stress testing will be estimated with an equation different than 220-(age).
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.