Mayo Clin Proc, January 2002, Vol 77
Autonomic Tone as a Cardiovascular Risk Factor
Autonomic Tone as a Cardiovascular Risk Factor:
The Dangers of Chronic Fight or Flight

Chronic imbalance of the autonomic nervous system is a
pertension also provide important lessons about the ad-
prevalent and potent risk factor for adverse cardiovascu-
verse effects of sympathetic predominance, as well as illus-
lar events, including mortality. Although not widely recog-
trate the benefits of β-blockers and angiotensin-converting
nized by clinicians, this risk factor is easily assessed by
enzyme inhibitors, 2 classes of drugs that reduce adrener-
measures such as resting and peak exercise heart rate,
gic tone. Other interventions, such as exercise, improve
heart rate recovery after exercise, and heart rate vari-
cardiovascular outcomes partially by increasing vagal ac-
ability. Any factor that leads to inappropriate activation
tivity and attenuating sympathetic hyperactivity.
of the sympathetic nervous system can be expected to have
Mayo Clin Proc. 2002;77:45-54
an adverse effect on these measures and thus on patient
outcomes, while any factor that augments vagal tone tends
to improve outcomes. Insulin resistance, sympathomimetic

ACE = angiotensin-converting enzyme; CCB = calcium chan-
medications, and negative psychosocial factors all have the
nel blocker; CHD = coronary heart disease; CHF = congestive
heart failure; LV = left ventricular; MI = myocardial infarc-

potential to affect autonomic function adversely and thus
tion; PPA = phenylpropanolamine
cardiovascular prognosis. Congestive heart failure and hy-
Evolutionary pressures over millions of years have ments to illicit or illegal drugs. Although these agents pro- adapted the sympathetic nervous system as a major duce short-term beneficial effects in many acute situations, mediator of the fight or flight response. Adrenergic neuro- long-term use not only results in tachyphylaxis but also humoral activation increases heart rate, blood pressure, and exacts a toll on the integrity of the cardiovascular system.
cardiac output and dilates large muscular arteries and the bronchioles. These changes are meant to prepare humansfor physical confrontation or to respond to acute hemody- The status of the autonomic nervous system, although namic collapse or respiratory compromise. When the sympa- often ignored by clinicians, is a major determinant of car- thetic nervous system is used in these settings, it improves a diovascular health and prognosis. Any therapy that chroni- person’s chance of survival and increases the likelihood that cally activates the sympathetic nervous system and/or di- his or her genes will be passed on to the next generation.
minishes parasympathetic (vagal) tone will increase the Appropriate and intermittent stimulation of the sympa- risk of cardiovascular events. In contrast, therapies that tip thetic nervous system produces immediate improvement in the autonomic balance toward parasympathetic dominance various symptoms, from the mundane (fatigue, weakness, and decrease sympathetic tone will improve prognosis.
nasal congestion, etc) to the more serious (bronchial con- This simple axiom explains many observations and should striction, hypotension, and shock). Additionally, some of the be used as a guide in clinical decision making in the diag- exhilaration of life is mediated by adrenergic stimulation, nosis and treatment of cardiovascular disease. In this ar- commonly referred to as an adrenaline rush. Conversely, a ticle, we review the relationship between autonomic tone reduction in sympathetic neurotransmitters such as dopa- and cardiovascular risk and suggest strategies for recogniz- mine and norepinephrine in the brain can produce dysphoria and lethargy. These factors have encouraged the liberal useof sympathomimetics for long-term therapy, ranging from prescription and over-the-counter drugs to “natural” supple- Many studies have established an elevated resting heartrate as a risk factor for cardiovascular disease and mortal- From the Mid-America Heart Institute of Saint Luke’s Hospital and ity.1,2 Astute clinicians have long recognized the paradoxi- the University of Missouri, Kansas City.
cally worrisome nature of a “normal” sinus rhythm of 90 Individual reprints of this article are not available. Address corre- beats/min compared with a reassuringly “abnormal” sinus spondence to James H. O’Keefe, Jr, MD, Cardiovascular Consul- tants, PC, 4330 Wornall Rd, Suite 2000, Kansas City, MO 64111 bradycardia of 50 beats/min. For example, the best prog- nostic marker on the admitting resting electrocardiogram 2002 Mayo Foundation for Medical Education and Research For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Autonomic Tone as a Cardiovascular Risk Factor
Mayo Clin Proc, January 2002, Vol 77
and are potent independent predictors of cardiovascular prognosis. Low heart rate variability has been associated with increased risk of coronary heart disease (CHD) and mortality,8,9 as well as with angiographic progression ofcoronary atherosclerosis10 and sudden cardiac death11 (Fig- ure 2). Data from the Framingham Heart Study confirm that heart rate variability is related to the risk of all-cause mortality12 and cardiac events.13 The ATRAMI (Auto- nomic Tone and Reflexes After Myocardial Infarction) study showed that both heart rate variability and baroreflex sensitivity were independent predictors of cardiovascular mortality.14 Heart rate variability can be estimated at the bedside by observing the variation in heart rate for 1 minuteduring deep breathing15 (Table 1).
HOW AUTONOMIC IMBALANCE INCREASES RISKSimple markers like peak exercise heart rate and heart ratevariability are powerful predictors of cardiovascular mor- Figure 1. The 5-year Kaplan-Meier survival estimates in 9454 tality because they are signs of an autonomic nervous patients according to deciles of heart rate recovery 1 minute afterexercise. Mortality was predicted by abnormal heart rate recov- system that has been disturbed by the strain of chronic, ery, hazard ratio of 4.16 (95% confidence interval, 3.33-5.19; excessive sympathetic tone. A dramatic example of this P<.001). Reprinted with permission from Nishime et al.6 phenomenon occurs under the extreme conditions of high-altitude mountain climbing. Elite alpinists are highlytrained athletes who at sea level have a resting heart rate of of a patient suffering an acute myocardial infarction (MI) is less than 55 beats/min, a peak exercise heart rate of greater the resting heart rate, not the extensiveness of Q waves or than 180 beats/min, and a brisk heart rate recovery within the first minute of resting. Within the days to weeks that Other indicators of the health of the autonomic system climbers are acclimating to progressively higher altitudes, can be detected on a routine exercise tolerance test. An their resting heart rate gradually increases, peak exercise impaired chronotropic response to exercise is defined as a heart rate decreases, and heart rate recovery becomes de- failure to achieve 85% of the age-predicted maximal heart layed.16,17 Altitudes greater than 26,000 feet are termed the rate. This abnormality is present in 11% to 26% of healthy death zone. As climbers ascend above this level, their middle-aged adults and increases mortality independent of resting heart rate typically increases to 120 to 140 beats/ findings on stress nuclear myocardial perfusion images and min, and their peak exercise heart rate decreases to this same level; thus, their heart rate recovery is nonexistent.
Heart rate recovery after exercise, which is mediated Essentially, climbers are dying of hypoxia and exposure, primarily by vagal tone, has also been shown to be a and the sympathetic nervous system, while trying to com- significant prognostic factor. In a study of 9500 people, pensate, is becoming less and less effective because of Nishime et al6 showed that failure to decrease heart rate by down-regulation of the adrenergic receptors in the face of more than 12 beats/min during the first minute after exer- continuous maximal sympathetic stimulation. These same cise (noted in 20% of apparently healthy middle-aged adaptations, although less extreme, operate under normal adults) increased mortality 4-fold over the ensuing 5 years (Figure 1). Another large study reported a relative risk of Excessive sympathetic stimulation and diminished va- mortality of 2.58 in one third of 5200 healthy adults who gal tone not only are markers of an unhealthy cardiovascu- had an abnormal heart rate recovery on a screening tread- lar system but also in part cause the adverse events.
Chronic sympathetic hyperactivity increases the cardiovas- Intact heart rate variability (beat-to-beat variability me- cular workload and hemodynamic stresses and predisposes diated by a dynamic autonomic nervous system, especially to endothelial dysfunction, coronary spasm, left ventricular vagal tone) and baroreflex sensitivity (reflex-mediated (LV) hypertrophy, and serious dysrhythmias.18 Increased changes in heart rate as a response to fluctuations in pre- vagal activity exerts a protective effect against ischemia- load and venous return, such as those noted during postural related dysrhythmias and also reduces heart rate and blood changes) are characteristics of a healthy autonomic system pressure.19 The risks of MI, sudden cardiac death, and For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
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Autonomic Tone as a Cardiovascular Risk Factor
stroke are highest during the first few hours after awaken-ing in the morning, correlating with the circadian peak in sympathetic activity.20 Mortality due to CHD is higher onMonday than on other days of the week but only in em-ployed people.21 β-Blockers normalize these increased risks related to circadian catecholamine peaks.22 In the setting of LV dysfunction, abnormal autonomic tone is the most sensitive predictor of cardiac and arrhyth- mic mortality, even more so than documented ventriculartachycardia.23 Major noncardiac surgery is associated withactivation of the sympathetic nervous system and increased CHD risk,24 and β-blockers normalize this perioperative The rates of sudden cardiac death and acute MI are increased in earthquake survivors during the days to weeks after the event. In a study of 12 patients who (by coin- cidence) were wearing a Holter monitor during a major earthquake in Taiwan, 9 showed enhanced sympathetic modulation and/or decreased vagal tone within 30 min- utes.27 Interestingly, the 3 people who did not show wors-ening autonomic tone were all taking a β-blocker at thetime of the earthquake.
Figure 2. Fractal analysis with use of the α-variable documentedheart rate variability as a powerful predictor of all-cause mortality In animal models, β-blockers decrease both stress-in- in 159 patients with depressed left ventricular function after acute duced and diet-induced atherosclerosis. Recently, in a 3- myocardial infarction. Impaired heart rate variability (α<.85) was year randomized placebo-controlled trial involving 793 pa- associated with a relative risk of 3.17 (P<.001). Reprinted with tients, low-dose metoprolol (25 mg/d) reduced progression of carotid atherosclerosis as effective as a statin.28 Clear-ly, autonomic imbalance is much more than a surrogate nomic neuropathy is common in patients with long-stand- ing poorly controlled diabetes and is associated with in-creased 5-year mortality.37 However, chronic hyperinsulin- emia, even in the absence of type 2 diabetes mellitus, is associated with heightened sympathetic tone and de- The mechanisms whereby traditional risk factors (such as smoking, unhealthy diet, obesity, and sedentary lifestyle) Data from the Framingham Heart Study recently con- predispose to adverse events are multifaceted, but activa- firmed that diabetes and impaired fasting glucose levels are tion of the sympathetic nervous system and diminished associated with reduced heart rate variability.40 Diabetic vagal tone appear to be important final common pathways patients have a 3- to 5-fold increased risk of sudden death through which a substantial portion of cardiovascular risk compared with nondiabetic patients.41 Although β-blockers is conferred.29 Some of the factors leading to chronic sym- tend to worsen insulin sensitivity, they decrease mortality pathetic activation are summarized in Table 2.
in diabetic patients partially by improving the autonomic Diabetes and the metabolic syndrome (hypertension, insulin resistance, obesity, and atherogenic dyslipidemia)adversely affect cardiac autonomic function and are associ- Table 1. Practical Clinical Indicators of
ated with increased risk of cardiovascular events.30-32 Abnormal Cardiac Autonomic Function
Elevated fasting insulin has been shown to increasesympathetic activity and heart rate33,34; the insulin resis- Resting heart rate greater than 90 beats/min tance syndrome also predisposes to cardiovascular hyper- Inability to achieve 85% of predicted maximal heart rate on responsiveness to sympathetic stimulation and has beenshown to reduce heart rate variability.35 A recent study Abnormal heart rate recovery (failure to decrease heart rate >12 beats/min during the first minute after peak exercise) showed that glucose intolerance was the strongest deter- Abnormal heart rate variability (failure to change heart rate, R-R minant of cardiovascular autonomic imbalance compared interval, by ≥10 beats/min during 1 minute of slow deep breaths) to the other standard risk factors.36 Symptomatic auto- For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Autonomic Tone as a Cardiovascular Risk Factor
Mayo Clin Proc, January 2002, Vol 77
Table 2. Factors Contributing to
between ephedra use and death was not proved in all cases, Chronic Sympathetic Activation
the National Football League policy was intended to protect the health of players until further study could be The Food and Drug Administration has been petitioned by the Public Citizen’s Health Research Group to ban all over-the-counter products containing ephedra. Data from the American Association of Poison Control Centers show that, between January 1993 and February 2000, supple- ments containing ephedra accounted for 42% of all the reported adverse events related to nutritional supplements During the 1980s, asthma-related mortality increased in association with the liberal use of β-agonists.52 Althoughthis association remains controversial,53 it has been estab-lished that even β -selective agents cause increased heart rate, decreased potassium levels, and increased QTc inter- Illicit, powerful sympathomimetic drugs like cocaine, val.54 These agents have been associated with ventricular methamphetamine, and 3,4-methylenedioxymethamphet- and atrial ectopy55 as well as increased risk of acute cardio- amine (also known as ecstasy) are popular because they vascular mortality.56 β-Agonists are used frequently in the produce a transient energized, euphoric state. Not sur- setting of an acute upper respiratory tract infection, which prisingly, these drugs markedly increase the risk of MI, has been independently associated with an increased risk of stroke, cardiomyopathy, dysrhythmias, and other adverse MI.57 A recent case-control study showed that the use of cardiovascular effects (particularly with long-term use).43-46 inhaled β-agonists was associated with an increased risk of Legal sympathomimetic medications are widely used for MI (adjusted odds ratio, 1.67; 95% confidence interval, various conditions, including weight loss, allergy or sinus 1.07-2.60) in patients with known cardiovascular disease.58 problems, asthma, and chronic lung disease. Sympathomi- Patients with chronic lung disease often use a β-agonist metic agents are often found in over-the-counter products, (albuterol) and an anticholinergic medication (ipratropium) including herbal preparations, and are frequently taken in concurrently. Anticholinergic medications can increase combination with other stimulants and without supervision.
heart rate and decrease heart variability.59 A case-control Two recently published studies (released early because study showed that, in patients with asthma, cardiovas- of public health implications) renewed concerns about the cular deaths were more common among those prescribed safety of nonprescription sympathomimetic medications.
ipratropium at discharge (odds ratio, 3.55; 95% confidence In the first study, phenylpropanolamine (PPA), often used interval, 1.05-11.94).60 A wide variety of medications have as a decongestant or appetite suppressant, was found to anticholinergic effects, and caution is advised when sym- increase the risk of hemorrhagic stroke in women.47 An pathomimetic and anticholinergic medications are used accompanying editorial estimated that as many as 200 to 400 strokes related to the use of PPA may occur annually inthe United States.48 As a result, the Food and Drug Admin- istration recommended that products containing PPA be removed voluntarily from the market. In a related study, Nowhere in medicine is the importance of the autonomic ephedra alkaloids, found in herbal preparations like ma nervous system more dramatic than in the patient with huang or Metabolife and used frequently for weight loss, congestive heart failure (CHF). Under the old paradigm, were found to be associated with various adverse cardio- the failing heart was “lazy” and needed sympathetic stimu- vascular and central nervous system effects, including hy- lation to improve systolic function and cardiac output.
Indeed, the normal heart will respond to sympathetic The National Football League recently banned ephedra stimulation by increasing cardiac output, but in the setting use because 4 players died in summer 2001 training camps; of an injured heart, adrenergic stimulation is analogous to 3 had ephedra in their bloodstream, and 1 had an ephedra- “flogging a sick horse.” A series of agents, from dopamine containing drink in his locker.50 Although a relationship and dobutamine decades ago to more recent designer For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
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Autonomic Tone as a Cardiovascular Risk Factor
inotropes with associated vasodilatation like milrinone orvesnarinone, showed transient, inconsistent improvements in CHF symptoms that were offset by an exacerbation (often doubling) of mortality over a 6- to 12-month period (Figure 3).61 Bouvy et al62 recently reported that use of sympathomimetic drugs increased the risk of hospitaliza- tion for arrhythmias in patients with CHF.
In contrast, the use of β-blockers has revolutionized the prognosis of cardiomyopathy and CHF. After an initial or ongoing insult to the myocardium, such as MI, un- controlled hypertension, excessive alcohol use, or viral myocarditis, the downward spiral of CHF is mediated by excessive sympathetic tone and activation of the renin- angiotensin system. This causes vasoconstriction, dys- rhythmias, apoptosis, and progressive LV dysfunction.18 Multiple studies have unequivocally documented that β-blockers are effective for improving outcomes in patients Figure 3. The Prospective Randomized Milrinone Survival Evalu- with CHF and LV dysfunction. These benefits have been ation (PROMISE) randomized 1088 patients with congestive found with carvedilol,63,64 bisoprolol,65 and metoprolol.66 β- heart failure (CHF) (class III or IV) to oral milrinone or placebo.
Blocker therapy not only reduces risk of sudden death but All-cause mortality was 28% higher in the patients taking also consistently increases systolic function better than any milrinone and 53% higher among those with class IV CHF (95% confidence interval, 13%-107%; P=.006). Reprinted with permis-sion from Packer et al.61 Because of the counterintuitive nature of the use of a β- blocker for the failing heart and the transient worsening ofsymptoms after initiation of therapy, many practicing phy- not only lower blood pressure but also reduce the risk sicians have been slow to embrace this life-saving therapy.
of adverse cardiovascular events beyond what would be Although β-blockers are the most important therapy for predicted based on the improvement in hypertension normalizing the prognosis of CHF, they are currently used in fewer than 1 in 5 eligible patients nationwide.
ACE inhibitors block activation of the renin-angiotensin system and indirectly decrease sympathetic tone.77,78 In the Heart Outcomes Prevention Evaluation (HOPE) trial, Sympathetic activity has been shown to be a factor in the ramipril decreased death, MI, and stroke, as well as the development of hypertension.68 When choosing an antihy- occurrence of new-onset diabetes.75 Other studies have pertensive agent, it is important to consider the autonomic shown that ACE inhibitors decrease sympathetic activation ramifications of the therapy. Direct vasodilators including in patients with chronic renal failure79 and CHF,80 as mea- short-acting calcium channel blockers (CCBs), particularly sured by muscle sympathetic nerve activity, and improve dihydropyridines such as nifedipine, cause a rapid decrease heart rate variability in diabetic patients.81 in blood pressure and a reflex increase in sympathetic β-Blockers lower heart rate and restore normal β-recep- activation, which may be associated with adverse cardio- tor responsiveness, improving peak exercise heart rate, vascular outcomes.69,70 Some studies have indicated that heart rate recovery, and beat-to-beat variability. β-Blockers patients treated with a short-acting CCB are at increased have also been shown to reduce the risk of sudden cardiac risk for MI and have a higher mortality rate than patients death by 30% to 50%82 and decrease all-cause mortality,83 treated with other types of medications.71,72 This increased especially in persons with an elevated resting heart rate risk appears to be limited to short-acting CCB agents.73 (indicating an activated sympathetic nervous system at Peripheral α-blockers (doxazosin, terazosin) lower blood pressure via peripheral vasodilation but activate thecentral sympathetic nervous system. In the Antihyperten- sive and Lipid-Lowering Treatment to Prevent Heart At- Psychosocial factors (like depression, anxiety, hostility, tack Trial (ALLHAT), doxazosin was found to increase and social isolation) increase CHD risk both by their asso- the risk of CHF and stroke compared to a diuretic.74 Drugs ciation with high-risk behaviors, such as smoking, and by that normalize sympathetic hyperactivity, like β-blockers direct pathophysiologic mechanisms, including activation and angiotensin-converting enzyme (ACE) inhibitors, of the sympathetic nervous system.85 Depression has been For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Autonomic Tone as a Cardiovascular Risk Factor
Mayo Clin Proc, January 2002, Vol 77
sudden cardiac death.95 Multiple studies support the rela- tionship between hostility96,97 or anger98 and CHD. Addi- tionally, lack of social support disturbs normal autonomic tone and is associated with increased risk of cardiovascularevents, in both healthy populations and those with known CHD.99-101 An exaggerated heart rate and blood pressure response to stressful situations, labeled the hot respondertrait, has been linked to an increased risk of cardiac In contrast, some lifestyle factors appear to be cardio- protective. The support provided by marriage,104 religiosity or faith,105 and other forms of social connection, such as dogownership, have been associated with activation of the para-sympathetic nervous system and decreased risk of future cardiovascular events. Interventions that have used psycho- social support programs for patients with CHD have shown mixed results, but some studies have shown benefit.106,107 Figure 4. The Metoprolol CR/XL Randomised Intervention Trialin Congestive Heart Failure (MERIT-HF) (3991 patients with Interventions for improving autonomic function are listed class II-IV congestive heart failure; ejection fraction ≤40%) in Table 3. In today’s world, sympathetic activation usually showed a reduction in all-cause mortality with controlled release/ occurs in response to emotional stress, but our body pre- extended release metoprolol, relative risk (RR), 0.66 (95% confi- pares as if it were responding to a physical threat. Increased dence interval [CI], 0.53-0.81; P<.001). Sudden death was also sympathetic tone that occurs with exercise is physiologic decreased, RR, 0.59 (95% CI, 0.45-0.78; P=.002). Reprinted withpermission from MERIT-HF Study Group.66 and facilitates increased capacity for physical work. Afterexertion, sympathetic tone is decreased from baseline, associated with elevated resting heart rate,86 decreased heart and vagal tone is augmented.108 This “relaxation response” rate variability,87 impaired vagal control,88 and elevated lev- does not occur after anxiety or extrinsic sympathomimetic els of plasma norepinephrine,89 suggesting chronic inappro- priate activation of the sympathetic nervous system. All 11 Although nonphysiologic stresses increase the risk of prospective studies evaluating a possible link between major adverse cardiovascular events, normal physiologic sympa- depression and CHD showed positive results.90 A history of thetic activation (eg, during exercise or sexual activity) major depression is a potent independent predictor for the improves physical conditioning, mood, and cardiovascular future risk of CHD events, with an odds ratio of approxi- prognosis. Exercise transiently stimulates the sympathetic mately 6.0, placing it among the strongest of cardiovascular nervous system, but because it strongly augments back- ground vagal activity, it is an effective and practical means Chronic anxiety has been shown to decrease heart rate to restore a healthy balance of autonomic tone.109 variability,93 impair vagal control,94 and increase the risk of The sympathetic activation that occurs during exercise can trigger sudden death or acute MI, predominantly in Table 3. Interventions to Improve Autonomic Function
sedentary persons and especially during extreme exer-tion.110 Thus, exercise has been referred to as a two-edged sword, increasing risk in the short term in susceptible per- sons, while reducing chronic risk in regular exercisers.111 Epidemiological studies have shown that physical activ- ity is important for reducing the risk of cardiovascular disease.112 Regular exercise is associated with lower resting heart rate and improved heart rate recovery.113,114 Regular physical activity also improves other indicators of auto- nomic function, including heart rate variability and baro- reflex sensitivity,19 and has been associated with decreased risk of sudden cardiac death115 and slower progression of carotid atherosclerosis.116 In a recent study, regular walking For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
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Autonomic Tone as a Cardiovascular Risk Factor
Lauer MS, Francis GS, Okin PM, Pashkow FJ, Snader CE, was shown to decrease blood pressure and sympathetic Marwick TH. Impaired chronotropic response to exercise stress nerve activity in men with mild hypertension.108 Frequent testing as a predictor of mortality. JAMA. 1999;281:524-529.
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