Prognostic value of heart rate responseto exercise






François CARRÉ, MD, PhD
Université Rennes 1
Hôpital Pontchaillou
INSERM U1099
Rennes, FRANCE

Prognostic value of heart rate response to exercise


by F. Carré, France



Exercise testing is commonly undertaken in cardiology for both diagnostic and prognostic purposes. Aside from the diagnostic criteria, new parameters have been proposed for improving the prognostic value of exercise testing, including kinetic analysis of heart rate changes during and after exercise. Three main parameters are currently proposed: chronotropic incompetence, heart rate recovery after exercise, and heart rate increase at the beginning of exercise. All of these are regulated by the autonomic nervous system, and abnormal values are linked to a decrease in parasympathetic effect and an increase in sympathetic effect. Chronotropic incompetence and heart rate recovery are currently the two easiest parameters to determine and are the most predictive. Both a low maximal heart rate and a decreased heart rate recovery are predictors of all-cause and cardiovascular mortality, both in healthy adults with or without risk factors, and in patients with coronary artery disease or heart failure. Their prognostic value is independent of the classical cardiovascular risk factors. Although chronotropic incompetence seems a stronger predictor of cardiovascular mortality than heart rate recovery, the risk seems most powerfully stratified when the two parameters are used together

Medicographia. 2012;34:407-413 (see French abstract on page 413)



Exercise testing is a very common test in cardiology, both for diagnostic and prognostic evaluation. Over the last decade, the classic exercise test used to predict adverse cardiovascular outcomes has evolved. The main parameters to initially be validated and used during exercise testing were electrocardiogram (ECG) alterations (mainly ischemic ST-segment depression) and hemodynamic changes.

Today, interpretation of the exercise test is no longer limited to these changes.1 Indeed, several other parameters have been validated and their value recognized. Fitness capacity is now well described as the best marker for life expectancy.2-4 The role of the autonomic nervous system in cardiac arrhythmia and survival after a cardiovascular event is also now well accepted.5 Frequent ventricular ectopy (mainly during recovery) appears to be associated with an increased death rate.6 Last, several studies have underlined the prognostic value of analyzing the kinetics of heart rate (HR) changes during and after an exercise test (reviewed in references 7-9).7-9 The aim of this short review is to clarify validated data in this area to enable proper use of these new parameters in the context of risk stratification and management of patients with cardiovascular diseases.

Heart rate adaptations to dynamic exercise in healthy people

The cardiovascular system plays a major role in the body’s adaptations to the acute hemodynamic and metabolic constraints imposed by physical exercise. These cardiovascular adaptations also play a major role in fitness capacity.

It is usual to describe two types of exercise; dynamic (or isotonic), and static (or isometric). Static exercise will not be discussed here, because the involvement of the cardiovascular system is quite minor. Dynamic exercise is characterized by alternating phases of contraction-relaxation of large skeletal muscle masses. It is performed with free ventilation, and its intensity gradually increases to a peak of effort, which corresponds to the individual maximum oxygen consumption (VO2 max).

Here, we shall focus on cardiac—in particular HR—adaptations observed during exercise and in the recovery phases of maximal dynamic exercise.9 During exercise, cardiac output gradually increases in line with exercise intensity (from 5 L/min to 20-25 L/min in healthy, sedentary people). Its main role is to increase the supply of oxygen to the skeletal muscles involved so that they can provide the energy requested. Cardiac output depends on two factors, HR and stroke volume. Stroke volume increases from the beginning of exercise, and it levels out at between 50% to 60% of VO2 max, which corresponds to a HR of 110-130 beats per minute (bpm) in healthy, sedentary people. Normally, HR increases throughout the exercise duration, producing two broadly different slopes before and after the leveling of the stroke volume.

Individual resting HR depends on intrinsic HR (HR observed after a double autonomic pharmacological blockade) and the effects of the autonomic nervous system. Intrinsic HR is determined by the phase IV depolarization of the action potential of pacemaker cells in the sinus node. Intrinsic HR is 100 to 110 bpm in young healthy people, and it gradually decreases with age (5 to 6 bpm per decade). This intrinsic HR is continuously regulated by the two arms of the autonomic nervous system (parasympathetic and sympathetic), which play the main role in HR regulation both at rest and during exercise. At rest, parasympathetic input slows the automatic discharge rate and acts as a brake, while sympathetic input, and blood catecholamines, act as an accelerator.9 Control of the autonomic nervous system is both centralized and reflexive. This double regulation allows rapid HR adaptation in cases of sudden stress, for example at the onset of physical exercise. It explains the fine regulation of the HR level to exercise intensity.

From the beginning of exercise, and sometimes before it (the anticipatory phase), the central autonomic control lifts the parasympathetic brake. This central effect is reinforced by the skeletal muscle reflexes, known as the exercise pressor reflex. These peripheral reflexes originate in contracting skeletal muscles. Mechano- and metabo-ergoreceptors activate these reflexes and thus continuously inform the cardiovascular control centers about the effort level.10 Thus, the initial HR increase is mainly due to the vagal “brake” release.7,11 Beyond 50% to 60% of VO2 max, HR increases linearly due to the combined effects of the sympathetic nervous system and circulating catecholamines. During the recovery phase, the HR decrease is exponential. Its initial fall (in 1 minute or less) is marked. It is mainly due to the fast slowdown vagal effect and is independent of the level of exercise intensity. The second phase of HR decrease is slower. It is mainly caused by the cessation of sympathetic nervous system activity and the delayed effects of circulating catecholamines.12,13

To summarize, during progressive and maximal dynamic exercise HR is regulated by the levels of parasympathetic and sympathetic activities and blood catecholamine levels. HR response to these factors also depends on the relative sensitivity of the sinoatrial node to catecholamines.

Heart rate regulation in chronic heart failure patients

It is interesting to note that this physiological relationship can be altered in cardiac patients.14 In patients with chronic heart failure, for example, several alterations of both the sinus node and its regulation by the autonomic nervous system have been reported. Indeed, chronic heart failure causes dysfunction of the sinoatrial and atrioventricular nodes. Intrinsic HR is thus decreased in heart failure. In experimental models, changes have been reported in the sensitivity of the sinoatrial node to acetylcholine and vagal nerve stimulation. These alterations are linked to extensive remodeling of ion channels, gap junction channels, ionic handling proteins, and receptors in the sinoatrial node.15 Impaired exercise-induced norepinephrine release associated with marked postsynaptic β-receptor desensitization influences HR regulation during exercise in these patients.15 The disturbances in autonomic balance can also create an electrically unstable substrate, which can play a role in the occurrence of arrhythmias.5,15

Thus, HR is the easiest component of the cardiovascular system to study continuously, noninvasively, and repeatedly during exercise testing. Kinetic analysis of HR provides an opportunity to study cardiovascular regulation by the autonomic nervous system at various phases of rest, exercise, and recovery. It therefore seems interesting and appropriate to investigate the ability of the autonomic nervous system to appropriately regulate HR during exercise.




Chronotropic incompetence as a prognostic factor for mortality and cardiac events

In 1972, the first data were reported showing that a low peak HR response during exercise was associated with an increased risk of cardiac death.7 It is now well accepted that chronotropic incompetence is associated with a worse prognosis for all-cause mortality and for both cardiac mortality and cardiac events (for example, myocardial infarction).16-26 This relationship is independent of the traditional cardiovascular risk factors and individual exercise capacity.7 The association has been reported in large populations of men and women of different ages (but mainly over 40 years of age), in otherwise healthy individuals, in those with or without known risk factors, and in those with coronary artery disease, post–myocardial infarction, and/or heart failure (see Table). The predictive value is observed in coronary patients and cardiac heart failure patients even when they are taking β-blockers.19-21,29 Moreover, in coronary patients, this predictive value is independent of the severity of coronary artery disease, and in patients with coronary artery bypass grafting, impaired chronotropic response to exercise identifies subjects at risk for worse clinical outcomes such as myocardial infarction, stroke, or graftocclusion.30,31 Maximal HR has also been proposed to calculate the ST segment/heart rate index (abnormal index >1.6 μV/bpm) to improve prediction of death from coronary artery disease in asymptomatic men.32 Chronotropic incompetence positively correlates with functional capacity in patients with mild and moderate cardiac heart failure and with diastolic dysfunction in healthy people.33,34 In subjects without apparent structural heart disease, chronotropic incompetence appears to be mainly induced by altered sympathetic activation that affects HR increase.35


Table
Table. Results of some of the main studies to have investigated the prognostic value of chonotropic incompetence (CI) and heart rate
recovery (HRR).

The percentages for maximum age-predicted peak heart rate (% Max-PPHR) and heart rate reserve (% HR reserve) were calculated with a cut-off of <80%. Duke Treadmill Score (DTS) index is defined as: (exercise time) - (5 x maximum ST-segment deviation) - (4 x treadmill angina index). Abbreviations: BB, β-blocker; CAD, coronary heart disease; CV, cardiovascular; HF, heart failure; pVO2, mixed venous oxygen tension; SD, sudden death.



Chronotropic incompetence produces a physiologically inappropriate HR response to metabolic demand. Several chronotropic incompetence indexes have been described, but the best method for clinical practice has not been established.8 Currently, there are three main widely used criteria.

The first, failure to achieve 80% to 85% of the maximum agepredicted HR, and the second, failure to achieve 80% of the HR reserve (maximal HR minus resting HR; or 100% agepredicted maximal HR minus resting HR) are usually closely associated. The reported prevalence of chronotropic incompetence in study populations is higher with the second criteria than the first.8 It must be noted that these two criteria are based on the assessment of maximal HR. The maximal HR of an individual must be determined during maximal effort with a symptom-limited exercise test. Several formulas have been proposed for the predicted value of maximal HR. Maximal HR depends mainly on age, but also on the ergometer used, and to a lesser extent on gender and fitness level. Briefly, maximal HR—which always decreases with age—is lower in women than in men, and is higher with treadmill exercise than with an ergocycle.25 Thus, an adapted equation for predicted maximal HR must be used for the two chronotropic incompetence indexes described above.

The third index is the chronotropic index, which takes into account age, physical fitness (exercise capacity), and resting HR. It quantifies the relationship between HR increment and oxygen consumption during exercise testing.8,25 The chronotropic index is the ratio of HR reserve to metabolic reserve. Age-predicted maximal HR is usually determined with the traditional formula of 220 – age (note that this formula was established with the ergocycle), although because of the aforementioned limits, a specifically adapted formula would seem more suitable. Ideally, individual metabolic reserve is calculated during a maximal cardiopulmonary exercise test with direct gas exchange analysis.8 Exercise capacity is estimated in metabolic equivalent tasks (METs; 1 MET = 3.5 ml/min/kg O2), and metabolic reserve is calculated as follows: (MET peak – 1)/(100% predicted MET peak – 1). The use of the chronotropic index enables evaluation of the chronotropic response at any stage of the exercise protocol. In healthy subjects, there is a direct and linear association between HR response and the metabolic work during exercise, and the chronotropic index is around 1.0. A lower chronotropic index is a sign of chronotropic incompetence. In healthy adults, a chronotropic index of <0.8 has been reported to be associated with a higher mortality risk.25

It is thus now well acknowledged that determination of the presence of chronotropic incompetence has important diagnostic, therapeutic, and prognostic implications, although the exact mechanism underlying chronotropic incompetence is at present unclear. Autonomic dysfunction involving an attenuated sympathetic drive during exercise occurring in subclinical cardiovascular disease, with or without early manifestation of cardiac ischemia, has been proposed as a potential explanation. These disturbances could favor lethal arrhythmias with an increased mortality risk in predisposed individuals.8,14

Heart rate recovery as a prognostic factor for mortality and cardiac events

There is increasing evidence that the recovery phase after exercise is a vulnerable period for cardiovascular events such as myocardial infarction, sudden cardiac death, and atrial fibrillation. Coactivation of both arms of the autonomic nervous system, which can occur during the recovery phase, may partly explain the clustering of various cardiovascular events in the recovery phase of exercise.13

Measurement of autonomic function via the study of HR during the early phase of recovery can provide prognostic information on cardiovascular events in both the general population and various patient groups, independent of classical cardiovascular risk factors (see Table).27,36-39 In coronary patients, for example, mortality was predicted by abnormal HR recovery (hazard ratio, 2.5; 95% confidence interval, [CI] 2.0- 3.1; P<0.0001) and by disease severity (hazard ratio, 2.0; 95% CI, 1.6-2.6; P<0.0001). Both variables gave additive and independent prognostic information.40 There is a significant correlation between abnormal postexercise HR recovery during the first minute (≤18 bpm) and both coronary artery calcium score (quantified with electron-beam computed tomography scanning) and the extent of major epicardial coronary involvement.41 Heart failure is also associated with blunted HR recovery after exercise, often in association with chronotropic incompetence, and it is more marked in severely affected patients with distinct echocardiographic, neurohormonal, and hemodynamic signs of the disease.42 Treatment with β-blockade has minimal impact on the prognostic power of HR recovery.21 In male veterans (n=5974), HR recovery at 2 minutes after treadmill exercise and low fitness were found to be associated with highermortality risk both together and independently. However, mortality risk was overestimated when exercise capacity was not considered. When both low fitness (≤6 METs) and low HR recovery (≤14 bpm) were present, mortality risk was approximately sevenfold higher than in highly fit and high–HR recovery subjects.43 Last, it is known that regular physical activity decreases sympathetic tone, and to a lesser extent increases parasympathetic tone, in healthy subjects and in patients. It was found that in patients undergoing exercise training in a phase II cardiac rehabilitation program, the increase in HR recovery after training was associated with an improvement in the prognosis for all-cause mortality. Conversely, persistence of abnormal HR recovery despite physical training is a marker of worse prognosis.44

Abnormal HR recovery is associated with several other altered functions. When used together, there seems to be an improvement in the power of risk prediction for all-cause and cardiovascular death in low-risk populations. Moreover, addition of both HR recovery and chronotropic incompetence to the Duke Treadmill Score improved (c-statistic from 0.61 to 0.68) the outcome prediction for all-cause mortality and nonfatal myocardial infarction in high-risk patients.45 Abnormal HR recovery and HR variability are both reduced in a parallel manner in coronary artery disease patients.41 Abnormal HR recovery is independently associated with diastolic dysfunction in subjects with normal systolic function at rest and during exercise. This relationship can be explained by the fact that diastolic dysfunction is partly due to an autonomic abnormality.34 The value of abnormal HR recovery as a predictor of mortality is improved when exercise capacity is also considered.43

Again, protocol methodology plays a major role in determining the prognostic value of HR recovery.46 First, the choice of the ergometer used for exercise testing is important, because individual values for maximal HR (maximal workload achievement) are higher when exercise is performed with a treadmill than with an ergocycle. Moreover, during the early phase of recovery, the drop in HR is slower after treadmill exercise.47 Indeed, in healthy subjects and heart failure patients, during active recovery after maximal exercise, recovery HR at 1minute after exercise is lower after cycle exercise than treadmill exercise.48 By contrast, HR recovery 2 and 3 minutes after the end of exercise does not differ as a function of the ergometer used.48 During stress echocardiography, because of the supine position of the exercise, HR decrease during the recovery phase is blunted compared with exercise in the standing or sitting position. Thus, to avoid false individual prognostic predictions, the absolute values proposed for chronotropic incompetence and abnormal HR recovery must be adapted to the ergometer used.47,49 Second, variations in the exercise termination protocol may play a role in the magnitude of HR recovery. The mode of recovery, passive or active, must be specified. It may be easier to use a passive mode of recovery, because an active mode can have many specifics (workload, speed, rate of pedaling).22 Third, both HR recovery at 1 and 2 minutes after exercise seem higher in men than in women.49 Fourth, although HR recovery at 1, 2, 3, 4, or 5 minutes after exercise have all been found to be inversely associated with death,37 the recovery duration investigated does play a role. Indeed, as previously described, HR recovery during the first minute of recovery is mediated primarily by vagal reactivation. It is almost independent of both sympathetic activity and exercise intensity. HR recovery in the second minute is affected by sympathetic nerve activity and exercise workload,47 and it appears that HR recovery during the second minute does provide the best prognostic value.43,49 Last, there is no true agreement in the literature about the “gold” cutoff value; whether ≤12 bpm or ≤18bpm for abnormal HR recovery during the first minute after exercise, or ≤22 bpm for abnormal passive HR recovery in the second minute after exercise.27,41,43,49

The precise mechanisms underlying the relationship between abnormalities in HR recovery and risk of mortality are not yet well understood. However, it is well known that impaired flow mediated vasodilation in peripheral arteries is closely correlated with endothelial dysfunction in coronary artery disease. There is an involvement between the sympathetic nervous system and endothelial function.41 It has been shown that HR recovery is significantly correlated with large artery stiffness, and in coronary artery disease patients, those with attenuated HR recovery show lower endothelium-dependent flow-mediated vasodilation.41,50 Thus, HR recovery seems to be a predictor of endothelial dysfunction that is independent of classical cardiovascular risk factors.

Initial heart rate response to exercise as a prognostic factor for mortality and cardiac events

Recently, some investigators have focused on the early HR response to exercise.51,52 Initially, a fast HR increase at the onset of exercise was linked to an increased risk of adverse cardiovascular events including cardiac death, especially in patients with coronary disease.51

In animals with previous myocardial infarction, a large HR increase at the onset of exercise was associated with a risk of developing ventricular fibrillation. This relationship was thought to be due to enhanced cardiac sympathetic activation.5 The results of a more recent study, however, performed in a large population tested with symptom-limited exercise testing on a treadmill for routine clinical indications showed the opposite; ie, that a large early rise in HR during exercise is associated with increased survival.52 This last result is in accordance with data suggesting that the early HR profile during exercise is mainly dominated by parasympathetic nervous tone.53 The higher the parasympathetic tone, the greater the HR rise early during exercise. The discrepancy observed between current studies may be due to the exercise protocols used. It seems that an individualized ramp protocol is best for studying individual HR profiles during exercise.52 Thus, the exact relationship between early HR changes in response to exercise and prognosis still remains to be determined in humans.

Many studies have demonstrated the prognostic value of dynamic exercise HR response parameters. Although further studies are needed to truly determine the most useful parameter and to explain its pathophysiological relationship with mortality, use of HR response parameters must be recommended when exercise testing is performed. Chronotropic incompetence and HR recovery are currently the two easiest parameters to determine and are the most predictive. Chronotropic incompetence appears to be a stronger predictor of cardiovascular mortality than HR recovery in patients referred for exercise testing for clinical reasons. However, when both parameters are used, the risk seems to be most powerfully stratified. _

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Keywords: autonomic nervous system; cardiovascular prognostic factor; chronotropic incompetence; coronary artery disease; exercise; heart failure; heart rate response; mortality risk factor