STATE-OF-THE-ART PAPER
Assessment of Autonomic Function in Cardiovascular DiseasePhysiological Basis and Prognostic Implications
Marc K. Lahiri, MD,
Prince J. Kannankeril, MD and
Jeffrey J. Goldberger, MD, FACC*
Division of Cardiology, Department of Medicine, Northwestern University, Chicago, Illinois.
Manuscript received October 10, 2007;
revised manuscript received December 20, 2007,
accepted January 6, 2008.
* Reprint requests and correspondence: Dr. Jeffrey J. Goldberger, Northwestern Memorial Hospital, 251 East Huron Street, Chicago, Illinois 60611-2950. (Email: j-goldberger{at}northwestern.edu).
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Abstract
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Certain abnormalities of autonomic function in the setting of structural cardiovascular disease have been associated with an adverse prognosis. Various markers of autonomic activity have received increased attention as methods for identifying patients at risk for sudden death. Both the sympathetic and the parasympathetic limbs can be characterized by tonic levels of activity, which are modulated by, and respond reflexively to, physiological changes. Heart rate provides an index of the net effects of autonomic tone on the sinus node, and carries prognostic significance. Heart rate variability, though related to heart rate, assesses modulation of autonomic control of heart rate and carries additional prognostic information, which in some cases is more powerful than heart rate alone. Heart rate recovery after exercise represents the changes in autonomic tone that occur immediately after cessation of exercise. This index has also been shown to have prognostic significance. Autonomic evaluation during exercise and recovery may be important prognostically, because these are high-risk periods for sudden death, and the autonomic changes that occur with exercise could modulate this high risk. These markers provide related, but not redundant information about different aspects of autonomic effects on the sinus node.
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Abbreviations and Acronyms
| | HF = high frequency | | HR = heart rate | | HRR = heart rate recovery | | HRV = heart rate variability | | LF = low frequency | | SDNN = standard deviation of normal R-R intervals | | VLF = very low frequency |
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Numerous experimental and clinical studies have demonstrated that certain measures of autonomic function in the setting of structural cardiovascular disease are associated with an adverse prognosis. Specifically, both increased sympathetic and decreased parasympathetic activity have been associated with an increased risk for sudden death and/or susceptibility to ventricular arrhythmias. For example, there is an increased incidence of reperfusion-induced ventricular fibrillation with sympathetic stimulation in dogs (1). Conversely, parasympathetic stimulation decreases the incidence of ventricular fibrillation during ischemia in exercising dogs with myocardial infarctions (MIs) (2). In humans, beta-blockers decrease the incidence of sudden cardiac death after MI and in patients with congestive heart failure (3–9). This link between the autonomic nervous system and sudden death has stimulated interest in the evaluation of autonomic function as a potential method for identifying patients at high risk for sudden death.
Although autonomic modulation of the cardiovascular system is likely to be important in the pathogenesis of sudden cardiac death, it remains difficult to measure or quantify. Although a simple relationship between a physiological marker and autonomic "activity" would be attractive, the autonomic nervous system is extremely complex, making it difficult to elucidate such a simple relationship. A variety of markers have been proposed to reflect autonomic "activity," including heart rate, heart rate variability, heart rate recovery after exercise, baroreflex sensitivity, heart rate turbulence, plasma/coronary sinus catecholamine levels, muscle sympathetic nerve activity, and others. Because heart rate can be measured noninvasively and inexpensively, much focus has been placed upon analysis of heart rate and heart rate variability. It is therefore important to relate these markers to their physiological counterparts to understand how abnormalities in these measures may be implicated in the pathogenesis of sudden cardiac death. In a stable physiological state, the sympathetic and parasympathetic limbs can be considered to have tonic levels of activity which generally have antagonistic effects. Spontaneous physiological processes, such as respiration, further modulate the tonic level of activity. Finally, tonic activity responds reflexively to various "stresses," such as changes in blood pressure via the baroreflex mechanism and exercise. The study of these physiological responses of the sinus node depend upon intact sinus node function.
In the present paper, we review the following methods of autonomic assessment: heart rate (HR), heart rate variability (HRV) and heart rate recovery after exercise (HRR), with an emphasis on the physiological basis for each marker. Their relationships to each other as well as their prognostic implications will be explored.
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HR
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The sinus node has an intrinsic rate of spontaneous depolarization, known as the intrinsic HR (10). The intrinsic HR is the HR measured in the absence of sympathetic and parasympathetic inputs (achieved by denervation or pharmacologic blockade). In healthy human subjects, this is approximately 100 beats/min and is age and gender dependent (10); endurance exercise-trained individuals may have a lower intrinsic HR (11). It is important to note that nonautonomic contributions to changes in HR exist: hypoxia, exercise, and temperature all can affect the intrinsic HR (12,13). Sympathetic and parasympathetic effects on the intrinsic HR predominantly determine the actual HR. Parasympathetic activation slows the HR via acetylcholine release from efferent vagal nerve discharge. In contrast, sympathetic activation accelerates the HR via circulating epinephrine, neural release of norepinephrine, or both (14). In a given stable physiological state, the sympathetic and parasympathetic inputs can be considered to have a tonic level of activity which determines the HR for that state. The influences of the sympathetic and parasympathetic nervous systems on HR have been proposed to be defined by the following formula: HR = m x n x HR0; where m is the sympathetic influence (>1), n is the parasympathetic influence (<1), and HR0 is the intrinsic HR (15). Thus, HR is determined by the intrinsic rate, and some measure of the tonic sympathetic and parasympathetic effects on the sinus node. Additionally, there are interactions between the sympathetic and parasympathetic limbs that determine their respective effects on HR. The effect of one limb is enhanced by increased activity of its counterpart, a phenomenon termed accentuated antagonism (16,17). In the absence of sympathetic activity, a given degree of parasympathetic stimulation will cause a given change in HR (from 100 to 90 beats/min, for example). The presence of sympathetic activity, though increasing HR (to 120 beats/min), allows the same degree of parasympathetic stimulation to cause a greater change in HR (from 120 to 105 beats/min).
Based on the model proposed by Rosenblueth and Simeone (15), HR seems to be a simple measure which can provide an index of the net effects of sympathetic and parasympathetic inputs to the sinus node. The HR consistently responds in an expected direction based on the underlying physiological state. That is, sympathetic stimulation consistently raises HR no matter what the stimulus is. Parasympathetic blockade raises HR, whereas parasympathetic stimulation lowers HR. In experimental settings, the R-R interval, reciprocally related to the HR, is directly related to vagal nerve activity (18). In a study of normal subjects exposed to a wide range of autonomic conditions, including upright tilt, exercise, epinephrine infusion, isoproterenol infusion, phenylephrine infusion, and parasympathetic blockade with atropine, HR responded in the expected direction for all subjects under all conditions tested (19). In the same study, none of the time and frequency domain measurements of HRV responded as consistently as the HR.
Although HR can be a powerful tool in the assessment of autonomic tone, it has obvious limitations. It provides a static index of the net effects of autonomic input to the sinus node, but no direct information regarding either sympathetic or parasympathetic input individually. For example, an HR of 110 beats/min demonstrates a net predominance of sympathetic effect on the sinus node. However, sympathetic stimulation, parasympathetic withdrawal, or various combinations of both may achieve this HR. Heart rate alone provides information regarding relative effects of autonomic tone in a given state, but not modulation or reflex activity.
The prognostic value of HR has been assessed in several large studies. High resting HR has been associated with increased all-cause mortality, death from cardiovascular disease, and particularly sudden cardiac death (20–23) in population-based studies. Jouven et al. (23) recently reported that a resting HR >75 beats/min in patients without clinical evidence of coronary disease conferred a nearly 4-fold risk for sudden cardiac death compared with those who had HR <60 beats/min over a 23-year follow-up period (23). Average HR on 24-h ambulatory electrocardiograms correlates with the incidence of new coronary events in patients with heart disease (24). In patients hospitalized with MI, high admission and discharge HRs are associated with an increase in both short- and long-term mortality (25–27). Comparison of trials of beta-blocker therapy after MI relates the reduction in resting HR to the percentage reduction in mortality in these trials (28). Thus, the simple measure of HR provides a global index of autonomic tone that has important prognostic significance. Despite the important role of HR and HR reduction in the prognosis of patients with cardiovascular disease, it is not widely recognized or used as a factor for risk assessment (29).
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HRV
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The oscillation in the intervals between consecutive heart beats has been described by several names, but heart rate variability has become the conventionally accepted term (30). Several methods of measuring the variation in HR have been developed, each of which falls under the broader description of being either "time domain" or "frequency domain" analyses. It should be noted that no one method has been identified as "superior" to the others, because no gold standard for HRV measurement exists; rather, these techniques may be considered to be complementary to each other. Time domain measures of HRV are assessed with calculations based on statistical operations on R-R intervals (31). Commonly used measures include standard deviation of normal R-R intervals (SDNN), the root mean square of successive R-R interval differences (MSSD), and the percentage of normal R-R intervals that differ by >50 ms (pNN50). Although all these are measures of HRV, they are not interchangeable, nor do they necessarily reflect similar physiology. For example, the SDNN is related to the total power (variance) whereas both MSSD and pNN50 detect high frequency oscillations. However, it should be noted that all HRV is substantially suppressed by parasympathetic blockade.
Frequency domain measures use spectral analysis of a sequence of R-R intervals and provide information on how power (variance) is distributed as a function of frequency. Short-term recordings (2 to 5 min) yield up to 3 peaks in very low (0.003 to 0.04 Hz; VLF), low (0.04 to 0.15 Hz; LF), and high (0.15 to 0.4 Hz; HF) frequency ranges. Long-term (24-h) recordings allow measurement of a fourth, ultralow (<0.003 Hz; ULF) frequency range. It is important to note that HRV measurements made from long-term recordings during which circadian rhythms are present and patient activity is not controlled provide different physiological information than HRV measurements made from short-term recordings during which conditions are typically controlled or stable. The LF and HF powers are often reported in normalized (relative or fractional) units, which represent the relative value of each power in proportion to the total power (usually minus the VLF component). This is done to minimize the effect of changes in total power on the value of HF and LF components. As will be described subsequently, the HF component is thought to reflect the modulation of vagus nerve discharge caused by respiration, whereas the LF and VLF components represent the variation in R-R interval caused by more gradual interplay between sympathetic and parasympathetic activities. The physiological basis for the ULF component is not well defined (29).
Newer nonlinear analysis techniques have been applied to further characterize HRV. Although the aforementioned traditional HRV methods characterize variability in R-R intervals within certain time scales or frequencies, nonlinear analyses describe the structure of the variability independently of the scale studied. This concept relates to the observation that whereas different fluctuation patterns are observed within specific time periods or frequencies (using traditional techniques), other self-similar fluctuation patterns may also be elicited from a broad range of data scales. Such methods gather information not detected by traditional techniques. For example, although a short-term recording of a patient's normal R-R intervals will have an identical SD as the same set of R-R intervals that are randomly shuffled, the underlying structure of these two sets of R-R intervals are completely different (32). It is this underlying pattern that nonlinear analysis methods attempt to describe.
Although the interplay between the sympathetic and parasympathetic inputs is different for each of the HF, LF, and VLF components of HRV, it appears that parasympathetic effects play a very important role in all of them. Respiratory sinus arrhythmia is a reflection of parasympathetic effects on the sinus node (33), and the HF component of HRV coincides with the respiratory frequency. Parasympathetic blockade with atropine results in >90% decrease in the power contained in this frequency (33), whereas beta-adrenergic blockade with propranolol does not alter the HF power significantly (34). Atropine also reduces HRV in the LF (34–36), which could be ascribed to blockade of vagally mediated fluctuations in HR provoked by sympathetically mediated changes in arterial pressure (37). Furthermore, parasympathetic blockade has also been shown to reduce the VLF component of HRV by 92% (38). The mechanism behind the vagal influence on the VLF component is not clear; fluctuations in the renin-angiotensin-aldosterone system as well as variations in thermoregulatory mechanisms have been speculated.
One reason for the association of each limb of the autonomic nervous system with a different frequency range stems from the fact that the timing of the HR response to autonomic nerve activity is not identical for each limb. Although a burst of vagal nerve activity has a maximal effect at 0.6 s with a return to baseline within 1 s, a sympathetic burst has no effect for 1 s, a maximal effect at 4 s, and a return to baseline within 20 s (39). Both cardiac and peripheral sympathetic responses have a similar time delay (40). The short delay of the vagal cardiac responses allows the parasympathetic nervous system to modulate HR at all frequencies between 0 and 0.5 Hz, although the sympathetic system has significant gain only below 0.15 Hz (41). Muscle sympathetic nerve activity has been shown to fluctuate every 10 s (42), a period long enough for vascular smooth muscle and sinus node effectors to respond to released norepinephrine and modulate blood pressure and HR (43). This period corresponds to the LF range observed in HRV. The absolute and normalized LF powers have therefore been used as an index of sympathetic modulation of the heart rate, and the ratio of absolute LF to HF power has been used as an index of "sympathovagal balance" (40,44), although this term is poorly defined (19,37). Upright tilt, which increases sympathetic tone predominantly due to an increase in direct neural stimulation (33), consistently increases LF and LF/HF power and decreases time domain measures of HRV (45); beta-blockade blunts these changes (40).
Although the idea of a simple relationship between components of HRV and sympathetic or parasympathetic tone is attractive, several studies indicate that the relationship is more complex. Despite the fact that in certain settings there appears to be a direct relationship between certain measures of HRV and either sympathetic or parasympathetic activity, there are many examples where these relationships degenerate. For example, different modes of beta-adrenergic activation (exercise, catecholamine infusion, and upright tilt) result in divergent changes in frequency domain indices which have been reported to reflect sympathetic activity (34). Partial parasympathetic blockade and baroreflex-mediated sympathetic withdrawal to similar degrees (as determined by HR) result in diminished HF power, but to different degrees (46). A 10-fold difference in HF power demonstrated at different respiratory rates between 0.4 and 0.1 Hz (24 to 6 breaths/min) despite similar HR again shows that HF power can vary greatly despite similar levels of parasympathetic effect (47) and underscores the role of modulation of HR as the determinant of HRV. Baroreflex-mediated increased parasympathetic activity with phenylephrine may actually decrease HF power and time domain measures at high levels of stimulation (48) owing to saturation of the HRV response (49). The complex relationship between HRV and parasympathetic effect was demonstrated in normal subjects after beta-blockade (50). Using baroreflex-mediated increases and decreases in parasympathetic tone, it was shown that HRV initially increases with increasing parasympathetic effect until it reaches a plateau. Beyond this, further increases in parasympathetic effect actually decrease HRV. Of note, marked interindividual variability in this relationship was noted. Therefore, HRV should be considered to be a technique that characterizes the modulation of autonomic tone. Although there is some relationship between the modulation of autonomic tone and its tonic effect, this relationship may be quite complex and individualized. It has also been shown that genetic factors may be important determinants of HRV (51,52). It is therefore difficult to relate specific HRV measurements to either sympathetic or parasympathetic tone.
The relationship between HR and HRV has been well studied. In an animal study, vagal nerve stimulation decreased HR, with a clear correlation between stimulation intensity and change in R-R interval (53). Vagal stimulation also increased time and frequency domain measurements of HRV, but with little to no correlation between HRV measures and stimulus intensity. Sympathetic stimulation increased HR, with an inverse correlation between R-R interval and stimulus intensity, but there was no significant effect on time or frequency domain measures of HRV. Thus, in this animal model, HR and HRV responded differently to parasympathetic and sympathetic stimulation. Several studies in humans have examined this relationship as well. In one study of healthy subjects, a moderate correlation between mean HR and time domain measures of HRV on 24-h ambulatory electrocardiograms was demonstrated (54). However, several other investigations in patients with coronary artery disease or heart failure found no significant correlation between mean, minimum, or maximum HR and time or frequency domain measures of HRV (55–57).
The prognostic significance of HRV in cardiovascular disease is widely reported. Decreased HRV has been associated with increased mortality in patients after MI, with heart failure, and with ischemic and idiopathic cardiomyopathy (58–65). Large epidemiologic studies have also linked an increased risk of coronary heart disease, death, and cardiac mortality with decreased HRV in general populations (66–68). Although it is clear that low HRV has a negative prognostic impact, it is important to point out that causality and mechanisms have not been established. Animal studies have shown that interventions which improve the HRV profile do not necessarily decrease risk for sudden death. In a study of post-infarction dogs at high risk for ventricular fibrillation during exercise and ischemia, the dogs were treated with intravenous scopolamine, which at low doses has a parasympathomimetic effect. Although scopolamine increased the time and frequency domain measures of HRV, there was no decreased risk of ventricular fibrillation (69). In contrast, exercise training in a similar canine model increased HRV and conferred protection from sudden death (70). The pathophysiological link between reduced HRV and increased mortality is unclear. In the recent DINAMIT (Defibrillator in Acute Myocardial Infarction Trial) (71), patients who had a recent MI, reduced ejection fraction, and impaired autonomic tone (as indicated by decreased HRV or high resting HR) did not have a survival benefit when treated with an implanted defibrillator, even though earlier studies have correlated early decreases in HRV within the first 48 h of MI with worse outcomes (72). On the other hand, cardiac resynchronization therapy with biventricular pacemakers has recently been shown to improve survival in a select group of patients with NYHA functional class III or IV heart failure and cardiac dyssynchrony (73). Although the exact mechanism of the benefit has not been identified, cardiac resynchronization therapy has been demonstrated to increase HRV (74); alterations in the autonomic modulation of the heart could play a role in the improved survival. This connection was further strengthened by a recent study of 113 patients with NYHA functional class III or IV heart failure, which found that those with improved time domain measures of HRV (by the SDNN method) 4 weeks after initiation of cardiac resynchronization therapy had better outcomes compared with those with less pronounced responses (75). Thus, HRV appears to be an important marker of mortality risk for sudden cardiac death, and some (but not all) interventions that improve HRV may also reduce the risk of sudden cardiac death. A causal relationship between low HRV and death has not been established.
Comparisons between the prognostic significance of HR versus HRV have been assessed in a few large studies. In a study of 808 patients after MI, HRV was an independent and better predictor of mortality compared with mean HR (58). A subsequent study, performed in the thrombolytic era, found that mean HR on 24-h recordings was nearly as good a predictor of all-cause mortality, as well as cardiac and sudden death, as HRV (76). In a study of 6,693 patients with 24-h Holter recordings, the adjusted relative risk for sudden death over a 2-year period was similar for low HRV and high minimum HR, but mean HR had no relation to sudden death (77).
Heart rate variability is a complex measure of modulation of HR that incorporates sympathetic effects, parasympathetic effects, and their interaction. Heart rate variability appears to be related to HR under certain conditions. It is an important marker of adverse prognosis in patients with cardiac disease and in normal populations. It is important to delineate the supplemental prognostic information contained in HRV over HR. Further understanding of the pathophysiological relationship of low HRV to mortality will be useful in developing strategies that could increase HRV and may improve survival.
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HR Recovery
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Exercise is associated with increased sympathetic and decreased parasympathetic activity (78–80). The period of recovery after exercise is accompanied by further dynamic changes in autonomic tone which are clinically characterized by the gradual return of HR to its previous resting level. This period of HRR results from a combination of sympathetic withdrawal and parasympathetic reactivation. Earlier studies have provided conflicting data as to which of these 2 processes plays the greater role in the physiology of early HRR. Savin et al. (81) studied the HRR of 6 men in whom selective autonomic blockade was administered on different days before the initiation of exercise. They interpreted their findings as suggesting that "sympathetic withdrawal contributes more to HRR soon after peak exercise cessation, with parasympathetic activation playing a greater role later in recovery at lower rates." In contrast, Imai et al. (82) reported that "the initial HRR within 30 seconds is mediated primarily by vagal reactivation." In that study, the investigators evaluated groups of young (age 20 years), trained athletes, older (age 55 years) subjects with congestive heart failure, and age-matched sedentary controls. Atropine was administered before exercise, and subjects exercised submaximally to anaerobic threshold. Heart rate recovery was evaluated only up to 2 min. More recent data also have demonstrated that parasympathetic activation plays a substantial role early in HRR after high-intensity exercise in normal subjects. Kannankeril et al. (83) analyzed HR in 10 healthy individuals during peak exercise and recovery under normal physiological conditions as well as during selective parasympathetic blockade with atropine. These data demonstrated that even during peak high-intensity exercise, the parasympathetic system has a small but significant effect on HR, indicating that parasympathetic withdrawal is not complete under such conditions. Upon cessation of exercise, augmentation of parasympathetic effects on HR occurred rapidly within the first minute. The intensity of parasympathetic reactivation steadily increased further until 4 min into recovery, after which time parasympathetic effects on HR remained relatively constant. The question of how much sympathetic withdrawal contributes to HRR after exercise was addressed in a recent study by Sundaram et al. (84). In that study, HRR after submaximal exercise was analyzed in 28 healthy subjects during normal physiological condition, as well as during selective beta-adrenergic blockade with propranolol, selective parasympathetic blockade with atropine, or double blockade with both agents. In the first minute of recovery, there was no difference in HRR between the conditions of parasympathetic blockade and double blockade, suggesting that beta-adrenergic withdrawal is not a significant factor in HRR within the first minute. Interestingly, there was a significant component of HRR seen in the group undergoing double blockade. This implies that there is a non–beta-adrenergic, nonparasympathetic component of HRR. Possible mechanisms could include changes in alpha-adrenergic tone, atrial stretch, or temperature changes. Collectively, these data suggest that early HRR after exercise is complex but predominantly due to parasympathetic reactivation, with sympathetic and nonautonomic components probably playing lesser roles.
There are compelling data to support the prognostic significance of HRR following exercise. Recently, Jouven et al. (23) reported that an HRR <25 beats/min after the first minute of recovery conferred a relative risk of 2.2 for sudden cardiac death compared with the highest-percentile HRR group (>40 beats/min) (23). In an earlier study, Cole et al. (85) defined an abnormal HRR as a decrease in HR from peak exercise to 1 min into recovery of 12 beats/min or less. In a cohort of 2,428 subjects without a prior history of heart failure, coronary revascularization, coronary angiography, or exercise testing, there was a 4-fold risk of death in those with abnormal HRR. After adjustment for age, gender, medications, perfusion defects on thallium scintigraphy, standard cardiac risk factors, resting HR, change in HR with exercise, and workload achieved, there was still a 2-fold risk of death in those with abnormal HRR. Though that study specifically investigated HRR after peak symptom-limited exercise, there are also data to suggest that impaired HRR after submaximal exercise has prognostic value as well. Cole et al. (86) defined abnormal HRR after submaximal exercise as a change of  42 beats/min from peak HR to that measured 2 min into recovery. In that study, patients with abnormal HRR after submaximal exercise incurred a relative risk of death of 2.58 during 12 years of follow-up. This increased risk remained significant after adjustment for standard risk factors, fitness, and resting and exercise HR. These data imply that HRR has prognostic implications under a broad range of exercise conditions. Furthermore, this prognostic value has been shown to represent risk independent of that based on the Duke Treadmill Score, suggesting that additive benefit may be derived from incorporating such measurements into standard treadmill test reporting (87). Interestingly, there is evidence that impaired HRR after exercise may be a modifiable risk factor. This was demonstrated in a recent study (88) that retrospectively studied HRR in 55 patients participating in phase II cardiac rehabilitation, an activity that has been shown to improve survival in patients following MI (89,90). The HRR was analyzed in 55 patients who had symptom-limited treadmill tests both before and after completing phase II cardiac rehabilitation. After completing cardiac rehabilitation, these patients had significantly lower resting HR compared with pre-rehabilitation measurements (65 beats/min vs. 69 beats/min; p = 0.01) and had a 26% improvement in their HRR during the first minute after exercise (15.4 beats/min pre-rehabilitation vs. 19.4 beats/min post-rehabilitation; p < 0.001). Such findings would suggest that cardiac rehabilitation improves parasympathetic function, which may at least in part contribute to the decreased mortality seen among these patients.
Why abnormal HRR after exercise is associated with an increased risk of death is not completely understood. One contributing factor could be that impaired HRR appears to correlate with the presence of underlying ischemic coronary artery disease. Georgoulias et al. (91) found that patients with impaired HRR (as defined by an HR decrease <21 beats/min 1 min after abrupt cessation of exercise) had a higher myocardial perfusion score (indicating more ischemia) on nuclear stress testing compared with patients with normal HRR. Therefore, patients with impaired HRR may be more likely to have underlying active ischemia, which could at least in part account for their higher mortality risk. However, ischemia does not appear to be the only factor contributing to their risk. In a prospective study of 2,935 patients who had both exercise testing and coronary angiography, Vivekananthan et al. (92) found that impaired HRR was predictive of mortality independent of the severity of coronary artery disease seen on angiography. Given the substantial role that parasympathetic activation plays in early recovery and the prognostic significance of diminished parasympathetic tone at rest, it is tempting to infer that parasympathetic "insufficiency" is implicated in the increased mortality risk in patients with abnormal HRR. However, there are no data that directly implicate diminished parasympathetic tone as the underlying mechanism behind the increased risk of death in such patients.
Heart rate recovery after exercise is emerging as a new and important prognostic index. Further investigation into the physiological basis and prognostic significance of autonomic function during recovery is warranted to better delineate its relation to the risk for total mortality and sudden cardiac death.
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Physiological Construct
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Given the wealth of information available regarding the physiological and prognostic significance of HR, HRV, and HRR, it is important to synthesize this information into a useful framework that can form the foundation for further study. The following simplified model may be useful to conceptualize autonomic control of HR and is shown schematically in Figure 1. Although it is likely that autonomic control of the HR also reflects autonomic effects on cardiac parameters other than the sinus node, it is important to recognize that there is differential innervation within the heart and that there may be differing effects in different regions of the heart (93).
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Figure 1 Schematic Diagram Showing Physiological Parasympathetic and Sympathetic Effects
This diagram shows the physiological parasympathetic and sympathetic effects on the sinus node to increase or decrease, respectively, the R-R interval and their interaction ("accentuated antagonism"). These inputs and their changes with physiological activities (i.e., respiration, exercise) influence the R-R interval, heart rate variability, and heart rate recovery. These characteristics can be quantified through short-term electrocardiogram (ECG) recordings, Holter monitoring, or stress testing. The heart rate, heart rate variability, and heart rate recovery that are measured through these tests provide prognostic information in patients with cardiovascular disease. Figure illustration by Rob Flewell.
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In its simplest formulation, HR is used to represent sympathovagal balance. Although this term is poorly defined, it is reasonable to use it as a measure of the net effects of the sympathetic and parasympathetic inputs into the sinus node. This concept is captured by HR. The HRV is then used to quantify the modulation of the sympathetic and parasympathetic inputs. The HRR represents the responsiveness and/or activity of the parasympathetic nervous system to cessation of exercise. Other parameters of the responsiveness of the autonomic system, such as baroreflex sensitivity and heart rate turbulence have also been shown to provide prognostic information. It should be noted that all of these techniques rely upon normal sinus node function and adequate recording of sinus node activity. The presence of sinus node dysfunction and significant atrial and/or ventricular ectopy in elderly patients with heart disease could make these measurements less useful.
Although it is likely that these indices and the related physiologies are dependent upon each other, they also each have distinct and independent physiological significance.
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Issues for Further Study
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Although there are compelling data that parasympathetic activity is associated with improved survival, the precise mechanism of parasympathetic protection is not clear. An attractive hypothesis is that parasympathetically induced changes in cardiac electrophysiology exert antiarrhythmic effects. It is well known that parasympathetic stimulation affects sinus nodal automaticity and AV nodal dromotropy (94,95). Several studies have also demonstrated changes in ventricular refractoriness with parasympathetic stimulation or blockade (96,97); parasympathetic effects on ventricular refractoriness may be antiarrhythmic. However, it is possible that some of the benefits of parasympathetic tone are mediated by other mechanisms, such as reduction in HR. Vanoli et al. (2) studied the effects of vagal stimulation and vagal stimulation plus atrial pacing on the prevention of exercise and ischemia-induced ventricular fibrillation in dogs with a healed MI. Although vagal stimulation prevented most episodes of ventricular fibrillation, when atrial pacing was instituted to prevent the HR reduction associated with vagal stimulation, approximately one-half of the animals had ventricular fibrillation. This suggests that the benefits of vagal stimulation may be partially due to an HR-lowering effect and partially due to other parasympathetic effects. It seems likely that most of these other protective effects of parasympathetic tone on sudden death would result from electrophysiological effects occurring in the ventricle. Yet, HR, HRV, and HRR all measure autonomic effects on the sinus node and may not provide adequate assessment of parasympathetic effects in the ventricle. Differential autonomic effects have been noted in various regions of the heart (93). Divergent changes in Q-T and R-R intervals (reflecting differential effects on ventricular repolarization and heart rate) beyond that simply explained by rate dependence can be observed in healthy subjects (98). Cervical vagal stimulation does not change HRV and BRS after vagal denervation of the atria in dogs, whereas changes in ventricular refractoriness are still induced (44). These studies highlight the fact that autonomic effects on the sinus node are not necessarily predictive of their effects on the ventricles.
The role of exercise and the associated changes in autonomic function in the pathophysiology of sudden death require further exploration. The risk of cardiac arrest and sudden death is substantially increased during and immediately after vigorous activity (99,100). Experimental data have shown that animals susceptible to ventricular fibrillation have greater reductions in HRV (parasympathetic modulation) during exercise compared with nonsusceptible animals (101). Interestingly, there was no significant difference between the 2 groups at rest. The HRR may provide further information regarding the risk for arrhythmias that occur in the setting of exercise or recovery.
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References
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1. Miyazaki T, Zipes D. Pericardial prostaglandin biosynthesis prevents the increased incidence of reperfusion-induced ventricular fibrillation produced by efferent sympathetic stimulation in dogs Circulation 1990;82:1008-1019.[Abstract/Free Full Text]2. Vanoli E, De Ferrari G, Stramba-Badiale M, Hull S, Foreman R, Schwartz P. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction Circ Res 1991;68:1471-1481.[Abstract/Free Full Text] 3. Wilhelmsson C, Vedin J, Wilhelmsson L, Tibblin G, Werko L. Reduction of sudden deaths after myocardial infarction by treatment with alprenolol Lancet 1974;2:1157-1160.[CrossRef][Web of Science][Medline] 4. Beta-Blocker Heart Attack Study Group A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 1982;247:1707-1714.[Abstract/Free Full Text] 5. Hjalmarson A. Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period Am J Cardiol 1997;80:35J-39J.[CrossRef][Medline] 6. Olsson G, Wikstrand J, Warnold I, et al. Metoprolol-induced reduction in mortality: pooled results from five double-blind randomized trials Eur Heart J 1992;13:28-32.[Abstract/Free Full Text] 7. Frishman W, Furberg C, Friedewald W. Beta-Adrenergic blockade for survivors of acute myocardial infarction N Engl J Med 1984;310:830-837.[Web of Science][Medline] 8. CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial Lancet 1999;353:9-13.[CrossRef][Web of Science][Medline] 9. MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet 1999;353:2001-2007.[CrossRef][Web of Science][Medline] 10. Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man Cardiovasc Res 1970;4:160-167.[Abstract/Free Full Text] 11. Smith M, Hudson S, Graitzer H, Raven P. Exercise training bradycardia: the role of autonomic balance Med Sci Sports Exerc 1989;21:40-44.[CrossRef][Web of Science][Medline] 12. Jose A, Stitt F. Effects of hypoxia and metabolic inhibitors on the intrinsic heart rate and myocardial contractility in dogs Circ Res 1969;25:53-66.[Abstract/Free Full Text] 13. Jose A, Stitt F, Collison D. The effects of exercise and changes in body temperature on the intrinsic heart rate in man Am Heart J 1970;79:488-498.[CrossRef][Web of Science][Medline] 14. Robertson D, Johnson G, Robertson R, Nies A, Shand D, Oats J. Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man Circulation 1979;59:637-643.[Abstract/Free Full Text] 15. Rosenblueth A, Simeone F. The interrelations of vagal and accelerator effects on the cardiac rate Am J Physiol 1934;110:42-55.[Free Full Text] 16. Levy M, Ng M, Martin P, Zieske H. Sympathetic and parasympathetic interactions upon the left ventricle of the dog Circ Res 1966;19:5-10.[Abstract/Free Full Text] 17. Levy M, Zieske H. Effect of enhanced contractility on the left ventricular response to vagus nerve stimulation in dogs Circ Res 1969;24:303-311.[Abstract/Free Full Text] 18. Katona PG, Poitras JW, Barnett GO, Terry BS. Cardiac vagal efferent activity and heart period in the carotid sinus reflex Am J Physiol 1970;218:1030-1037.[Free Full Text] 19. Goldberger J. Sympathovagal balance: how should we measure it? Am J Physiol 1999;276:H1273-H1280.[Web of Science][Medline] 20. Kannel W, Kannel C, Paffenbarger R, Cupples P, Cupples L. Heart rate and cardiovascular mortality: the Framingham Study Am Heart J 1987;113:1489-1494.[CrossRef][Web of Science][Medline] 21. Gillum R, Makuc D, Feldman J. Pulse rate, coronary heart disease, and death: the NHANES I epidemiologic follow-up study Am Heart J 1991;121:172-177.[CrossRef][Web of Science][Medline] 22. Shaper A, Wannamethee G, Macfarlane P, Walker M. Heart rate, ischaemic heart disease, and sudden cardiac death in middle-aged British men Br Heart J 1993;70:49-55.[Abstract/Free Full Text] 23. Jouven X, Empana J, Schwartz P, Desnos M, Courbon D, Ducimetiere P. Heart-rate profile during exercise as a predictor of sudden death N Engl J Med 2005;352:1951-1958.[Abstract/Free Full Text] 24. Aronow W, Ahn C, Mercando A, Epstein S. Association of average heart rate on 24-hour ambulatory electrocardiograms with incidence of new coronary events at 48-month follow-up in 1,311 patients (mean age 81 years) with heart disease and sinus rhythm Am J Cardiol 1996;78:1175-1176.[Web of Science][Medline] 25. Hjalmarson A, Gilipin E, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction Am J Cardiol 1990;65:547-553.[CrossRef][Web of Science][Medline] 26. Disegni E, Goldbourt U, Reicher-Reiss H, et al. SPRINT Study Group (Secondary Prevention Reinfarction Israeli Nifedipine Trial) The predictive value of admission heart rate on mortality in patients with acute myocardial infarction J Clin Epidemiol 1995;48:1197-1205.[CrossRef][Web of Science][Medline] 27. Zuanetti G, Mantini L, Hernandez-Bernal F, et al. Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study Eur Heart J 1998;19:F19-F26.[CrossRef][Web of Science][Medline] 28. Kjekshus J. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials Am J Cardiol 1986;57:43F-49F.[CrossRef][Medline] 29. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease J Am Coll Cardiol 2007;50:823-830.[Abstract/Free Full Text] 30. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology Heart rate variability: standards of measurement, physiological interpretation, and clinical use Circulation 1996;93:1043-1065.[Free Full Text] 31. Kleiger RE, Stein PK, Bosner MS, Rottman JN. Time domain measurements of heart rate variability Cardiol Clin 1992;10:487-498.[Medline] 32. Stein PK, Domitrovich PP, Huikuri HV, Kleiger RE. Traditional and nonlinear heart rate variability are each independently associated with mortality after myocardial infarction J Cardiovasc Electrophysiol 2005;16:13-20.[CrossRef][Web of Science][Medline] 33. Goldberger J, Kadish A. Influence of sympathetic and parasympathetic maneuvers on heart rate variabilityIn: Moss A, Stern S, editors. Noninvasive Electrocardiology: Clinical Aspects of Holter Monitoring. London, United Kingdom: W.B. Saunders; 1995. pp. 207-223. 34. Ahmed M, Kadish A, Parker M, Goldberger J. Effect of physiologic and pharmacologic adrenergic stimulation on heart rate variability J Am Coll Cardiol 1994;24:1082-1090.[Abstract] 35. Koh J, Brown T, Beightol L, Ha C, Eckberg D. Human autonomic rhythms: vagal cardiac mechanisms in tetraplegic subjects J Physiol 1994;474:483-495.[Abstract/Free Full Text] 36. Pomeranz B, Macaulay RJB, Caudill MA, et al. Assessment of autonomic function in humans by heart rate spectral analysis Am J Physiol 1985;248:H151-H153.[Web of Science][Medline] 37. Eckberg D. Sympathovagal balance: a critical appraisal Circulation 1997;96:3224-3232.[Free Full Text] 38. Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR-interval oscillations in humans Circulation 1998;98:547-555.[Abstract/Free Full Text] 39. Spear J, Kronhaus K, Moore E, Kline R. The effect of brief vagal stimulation on the isolated rabbit sinus node Circ Res 1979;44:75-88.[Abstract/Free Full Text] 40. Pagani M, Lombardi F, Guzzetti S, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog Circ Res 1986;59:178-193.[Abstract/Free Full Text] 41. Berntson G, Bigger J, Eckberg D, et al. Heart rate variability: origins, methods, and interpretive caveats Psychophysiol 1997;34:623-648.[Web of Science][Medline] 42. Saul JP, Rea RF, Eckberg DL, Berger RD, Cohen RJ. Heart rate and muscle sympathetic nerve variability during reflex changes of autonomic activity Am J Physiol 1990;258:H713-H721.[Web of Science][Medline] 43. Wallin B, Nerhed C. Relationship between spontaneous variations of muscle sympathetic activity and succeeding changes of blood pressure in man J Auton Nerv Syst 1982;6:293-302.[CrossRef][Web of Science][Medline] 44. Chiou C, Zipes D. Selective vagal denervation of the atria eliminates heart rate variability and baroreflex sensitivity while preserving ventricular innervation Circulation 1998;98:360-368.[Abstract/Free Full Text] 45. Vybiral T, Bryg RJ, Maddens ME, Boden WE. Effect of passive tilt on sympathetic and parasympathetic components of heart rate variability in normal subjects Am J Cardiol 1989;63:1117-1120.[CrossRef][Web of Science][Medline] 46. Challapalli S, Kadish A, Horvath G, Goldberger J. Differential effects of parasympathetic blockade and parasympathetic withdrawal on heart rate variability J Cardiovasc Electrophysiol 1999;10:1192-1199.[CrossRef][Web of Science][Medline] 47. Brown T, Beightol L, Koh J, Eckberg D. Important influence of respiration on human R-R interval power spectra is largely ignored J Appl Physiol 1993;75:2310-2317.[Abstract/Free Full Text] 48. Goldberger J, Ahmed M, Parker M, Kadish A. Dissociation of heart rate variability from parasympathetic tone Am J Physiol 1994;266:H2152-H2157.[Web of Science][Medline] 49. Malik M, Camm A. Components of heart rate variability—what they really mean and what we really measure Am J Cardiol 1993;72:821-822.[CrossRef][Web of Science][Medline] 50. Goldberger J, Challapalli S, Tung R, Parker M, Kadish A. Relationship of heart rate variability to parasympathetic effect Circulation 2001;103:1977-1983.[Abstract/Free Full Text] 51. Singh J, Larson M, O'Donnel C, Tsuji J, Evans J, Levy D. Heritability of heart rate variability: the Framingham Heart Study Circulation 1999;99:2251-2254.[Abstract/Free Full Text] 52. Kupper N, Willemsen G, Van de Berg M, et al. Heritability of ambulatory heart rate variability Circulation 2004;110:2792-2796.[Abstract/Free Full Text] 53. Bailey J, Fitzgerald D, Applegate R. Effects of constant cardiac autonomic nerve stimulation on heart rate variability Am J Physiol 1996;270:H2081-H2087.[Medline] 54. Van Hoogenhuyze D, Weinstein N, Martin G, et al. Reproducibility and relation to mean heart rate of heart rate variability in normal subjects and in patients with congestive heart failure secondary to coronary artery disease Am J Cardiol 1991;68:1668-1676.[CrossRef][Web of Science][Medline] 55. Panina G, Khot U, Nunziata E, Cody R, Binkley P. Assessment of autonomic tone over a 24-hour period in patients with congestive heart failure: relation between mean heart rate and measures of heart rate variability Am Heart J 1995;129:748-753.[CrossRef][Web of Science][Medline] 56. Madias J, Wijetilaka R, Erteza S, et al. Correlative studies of heart rate and heart rate variability indices from five consecutive ambulatory electrocardiogram recordings in patients with coronary artery disease Clin Cardiol 1996;19:939-944.[Web of Science][Medline] 57. Adamopoulos S, Piepoli M, McCance A, et al. Comparison of different methods for assessing sympathovagal balance in chronic congestive heart failure secondary to coronary artery disease Am J Cardiol 1992;70:1576-1582.[CrossRef][Web of Science][Medline] 58. Kleiger RE, Miller P, Bigger JT, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction Am J Cardiol 1987;59:256-262.[CrossRef][Web of Science][Medline] 59. Lanza G, Guido V, Galeazzi M, et al. Prognostic role of heart rate variability in patients with recent acute myocardial infarction Am J Cardiol 1998;82:1323-1328.[CrossRef][Web of Science][Medline] 60. Nolan J, Batin P, Andrews R, et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom Failure Evaluation and Assessment of Risk Trial (UK-HEART) Circulation 1998;98:1510-1516.[Abstract/Free Full Text] 61. Ponikowski P, Anker S, Chua T, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy Am J Cardiol 1997;79:1645-1650.[CrossRef][Web of Science][Medline] 62. Bigger J, Fleiss J, Rolnitzky L, Steinman R. Frequency domain measures of heart period variability to assess risk late after myocardial infarction J Am Coll Cardiol 1993;21:729-736.[Abstract] 63. Galinier M, Pathak A, Fourcade J, et al. Depressed low frequency power of heart rate variability as an independent predictor of sudden death in chronic heart failure Eur Heart J 2000;21:475-482.[Abstract/Free Full Text] 64. La Rovere MT, Pinna GD, Maestri R, et al. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients Circulation 2003;107:565-570.[Abstract/Free Full Text] 65. Rashba EJ, Estes NA, Wang P, et al. Preserved heart rate variability identifies low-risk patients with nonischemic dilated cardiomyopathy: results from the DEFINITE trial Heart Rhythm 2006;3:281-286.[CrossRef][Web of Science][Medline] 66. Dekker J, Crow R, Folsom A, et al. Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC study Circulation 2000;102:1239-1244.[Abstract/Free Full Text] 67. de Bruyne M, Kors J, Hoes A, et al. Both decreased and increased heart rate variability on the standard 10-second electrocardiogram predict cardiac mortality in the elderly: the Rotterdam Study Am J Epidemiol 1999;150:1282-1288.[Abstract/Free Full Text] 68. Tsuji H, Larson M, Venditti F, et al. Impact of reduced heart rate variability on risk for cardiac events Circulation 1996;94:2850-2855.[Abstract/Free Full Text] 69. Hull S, Vanoli E, Adamson P, Ferrari GD, Foreman R, Schwartz P. Do increases in markers of vagal activity imply protection from sudden death Circulation 1995;91:2516-2519.[Abstract/Free Full Text] 70. Hull S, Vanoli E, Adamson P, Verrier R, Robert D, Schwartz P. Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia Circulation 1994;89:548-552.[Abstract/Free Full Text] 71. Hohnloser S, Kuck K, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction N Engl J Med 2004;351:2481-2488.[Abstract/Free Full Text] 72. Carpeggiani C, L'Abbate A, Landi P, et al. Early assessment of heart rate variability is predictive of in-hospital death and major complications after acute myocardial infarction Int J Cardiol 2004;96:361-368.[CrossRef][Web of Science][Medline] 73. Cleland J, Daubert J, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure N Engl J Med 2005;352:1539-1549.[Abstract/Free Full Text] 74. Adamson P, Kleckner K, Van Hout W, Srinivasam S, Abraham W. Cardiac resynchronization therapy improves heart rate variability in patients with symptomatic heart failure Circulation 2003;108:266-269.[Abstract/Free Full Text] 75. Fantoni C, Raffa S, Regoli F, et al. Cardiac resynchronization therapy improves heart rate profile and heart rate variability of patients with moderate to severe heart failure J Am Coll Cardiol 2005;46:1875-1882.[Abstract/Free Full Text] 76. Copie X, Hnatkova K, Staunton A, Fei L, Camm A, Malik M. Predictive power of increased heart rate versus depressed left ventricular ejection fraction and heart rate variability for risk stratification after myocardial infarction J Am Coll Cardiol 1996;27:270-276.[Abstract] 77. Algra A, Tijssen J, Roelandt J, Pool J, Lubsen J. Heart rate variability from 24-hour electrocardiography and the 2-year risk for sudden death Circulation 1993;88:180-185.[Abstract/Free Full Text] 78. Robinson B, Epstein S, Beiser G, Braunwald E. Control of heart rate by the autonomic nervous system: studies in man on the interrelation between baroreceptor mechanisms and exercise Circ Res 1966;19:400-411.[Abstract/Free Full Text] 79. Ekblom R, Goldbarg A, Kilbom A, Astrand P. Effects of atropine and propranolol on the oxygen transport system during exercise in man Scand J Clin Lab Invest 1972;30:35-42.[Web of Science][Medline] 80. Fagraeus L, Linnarsson D. Autonomic origin of heart rate fluctuations at the onset of muscular exercise J Appl Physiol 1976;40:679-682.[Abstract/Free Full Text] 81. Savin W, Davidson D, Haskell W. Autonomic contribution to heart rate recovery from exercise in humans J Appl Physiol 1982;53:1572-1575.[Abstract/Free Full Text] 82. Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure J Am Coll Cardiol 1994;24:1529-1535.[Abstract] 83. Kannankeril P, Le F, Kadish A, Goldberger J. Parasympathetic effects on heart rate recovery after exercise J Investig Med 2004;52:394-401.[Web of Science][Medline] 84. Sundaram S, Shoushtari C, Carnethon M, Kadish A, Goldberger J. Autonomic and nonautonomic determinants of heart rate recovery Heart Rhythm 2004;1:S100-S101. 85. Cole C, Blackstone E, Pashkow F, Snader C, Lauer M. Heart-rate recovery immediately after exercise as a predictor of mortality N Engl J Med 1999;341:1351-1357.[Abstract/Free Full Text] 86. Cole C, Foody J, Blackstone E, Lauer M. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort Ann Intern Med 2000;132:552-555.[Abstract/Free Full Text] 87. Nishime E, Cole C, Blackstone E, Pashkow F, Lauer M. Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG JAMA 2000;284:1392-1398.[Abstract/Free Full Text] 88. Hao S, Chai A, Kligfield P. Heart rate recovery response to symptom-limited treadmill exercise after cardiac rehabilitation in patients with coronary artery disease with and without recent events Am J Cardiol 2002;90:763-765.[CrossRef][Web of Science][Medline] 89. Oldridge N, Guyatt G, Fischer M, Rimm A. Cardiac rehabilitation after myocardial infarction. Combined experience of randomized clinical trials. JAMA 1988;260:945-950.[Abstract/Free Full Text] 90. O'Connor G, Buring J, Yusuf S, et al. An overview of randomized trials of rehabilitation with exercise after myocardial infarction Circulation 1989;80:234-244.[Abstract/Free Full Text] 91. Georgoulias P, Orfanakis A, Demakopoulos N, et al. Abnormal heart rate recovery immediately after treadmill testing: correlation with clinical, exercise testing, and myocardial perfusion parameters J Nucl Cardiol 2003;10:498-505.[CrossRef][Web of Science][Medline] 92. Vivekananthan D, Blackstone E, Pothier C, Lauer M. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease J Am Coll Cardiol 2003;42:831-838.[Abstract/Free Full Text] 93. Pickoff A, Stolfi A. Modulation of electrophysiological properties of neonatal canine heart by tonic parasympathetic stimulation Am J Physiol 1990;258:H38-H44.[Web of Science][Medline] 94. Furukawa Y, Wallick D, Carlson M, Martin P. Cardiac electrical responses to vagal stimulation Am J Physiol 1990;258:H1112-H1118.[Web of Science][Medline] 95. Goldberger J, Kadish A, Johnson D, Qi X. New technique for vagal nerve stimulation J Neurosci Methods 1999;91:109-114.[CrossRef][Web of Science][Medline] 96. Litovsky S, Antzelevitch C. Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol: a direct effect of acetylcholine in ventricular myocardium Circ Res 1990;67:615-627.[Abstract/Free Full Text] 97. Prystowsky E, Jackman W, Rinkenberger R, Heger J, Zipes D. Effect of autonomic blockade on ventricular refractoriness and atrioventricular nodal conduction in humans: evidence supporting a direct cholinergic action on ventricular muscle refractoriness Circ Res 1981;49:511-518.[Free Full Text] 98. Kowallik P, Braun C, Meesman M. Independent autonomic modulation of sinus node and ventricular myocardium in healthy young men during sleep J Cardiovasc Electrophysiol 2000;11:1063-1070.[CrossRef][Web of Science][Medline] 99. Siscovick D, Weiss N, Fletcher R, Lasky T. The incidence of primary cardiac arrest during vigorous exercise N Engl J Med 1984;311:874-877.[Abstract] 100. Albert C, Mittleman M, Chae C, Lee I, Hennekens C, Manson J. Triggering of sudden death from cardiac causes by vigorous exertion N Engl J Med 2000;343:1355-1361.[Abstract/Free Full Text] 101. Billman G, Hoskins R. Time-series analysis of heart rate variability during submaximal exercise: evidence for reduced cardiac vagal tone in animals susceptible to ventricular fibrillation Circulation 1989;80:146-157.[Abstract/Free Full Text]
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