Autonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight

doi:10.4065/77.1.45

Mayo Clinic Proceedings

Volume 77, Issue 1, January 2002, Pages 45-54

https://doi.org/10.4065/77.1.45 Get rights and content

Chronic imbalance of the autonomic nervous system is a prevalent and potent risk factor for adverse cardiovascular events, including mortality. Although not widely recognized by clinicians, this risk factor is easily assessed by measures such as resting and peak exercise heart rate, heart rate recovery after exercise, and heart rate variability. Any factor that leads to inappropriate activation of the sympathetic nervous system can be expected to have 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 medications, and negative psychosocial factors all have the potential to affect autonomic function adversely and thus cardiovascular prognosis. Congestive heart failure and hypertension also provide important lessons about the adverse effects of sympathetic predominance, as well as illustrate the benefits of β-blockers and angiotensin-converting enzyme inhibitors, 2 classes of drugs that reduce adrenergic tone. Other interventions, such as exercise, improve cardiovascular outcomes partially by increasing vagal activity and attenuating sympathetic hyperactivity.

Section snippets

AUTONOMIC DYSFUNCTION AS A RISK FACTOR

Many studies have established an elevated resting heart rate as a risk factor for cardiovascular disease and mortality.1, 2 Astute clinicians have long recognized the paradoxically worrisome nature of a “normal” sinus rhythm of 90 beats/min compared with a reassuringly “abnormal” sinus bradycardia of 50 beats/min. For example, the best prognostic marker on the admitting resting electrocardiogram of a patient suffering an acute myocardial infarction (MI) is the resting heart rate, not the

HOW AUTONOMIC IMBALANCE INCREASES RISK

Simple markers like peak exercise heart rate and heart rate variability are powerful predictors of cardiovascular mortality because they are signs of an autonomic nervous system that has been disturbed by the strain of chronic, excessive sympathetic tone. A dramatic example of this phenomenon occurs under the extreme conditions of high-altitude mountain climbing. Elite alpinists are highly trained athletes who at sea level have a resting heart rate of less than 55 beats/min, a peak exercise

INSULIN RESISTANCE AND AUTONOMIC DYSFUNCTION

The mechanisms whereby traditional risk factors (such as smoking, unhealthy diet, obesity, and sedentary lifestyle) predispose to adverse events are multifaceted, but activation of the sympathetic nervous system and diminished vagal tone appear to be important final common pathways through which a substantial portion of cardiovascular risk is conferred.²⁹ Some of the factors leading to chronic sympathetic activation are summarized in Table 2.

Diabetes and the metabolic syndrome (hypertension,

RISKS OF SYMPATHOMIMETIC DRUGS

Illicit, powerful sympathomimetic drugs like cocaine, methamphetamine, and 3,4-methylenedioxymethamphet-amine (also known as ecstasy) are popular because they produce a transient energized, euphoric state. Not surprisingly, these drugs markedly increase the risk of MI, stroke, cardiomyopathy, dysrhythmias, and other adverse cardiovascular effects (particularly with long-term use).43, 44, 45, 46 Legal sympathomimetic medications are widely used for various conditions, including weight loss,

β-AGONIST BRONCHODILATORS

During the 1980s, asthma-related mortality increased in association with the liberal use of β-agonists.⁵² Although this association remains controversial,⁵³ it has been established that even β₂-selective agents cause increased heart rate, decreased potassium levels, and increased QTc interval.⁵⁴ These agents have been associated with ventricular and atrial ectopy⁵⁵ as well as increased risk of acute cardiovascular mortality.⁵⁶ β-Agonists are used frequently in the setting of an acute upper

LESSONS LEARNED FROM CONGESTIVE HEART FAILURE

Nowhere in medicine is the importance of the autonomic nervous system more dramatic than in the patient with congestive heart failure (CHF). Under the old paradigm, the failing heart was “lazy” and needed sympathetic stimulation to improve systolic function and cardiac output. Indeed, the normal heart will respond to sympathetic stimulation by increasing cardiac output, but in the setting of an injured heart, adrenergic stimulation is analogous to “flogging a sick horse.” A series of agents,

CHOICE OF AGENTS FOR HYPERTENSION

Sympathetic activity has been shown to be a factor in the development of hypertension.⁶⁸ When choosing an antihy-pertensive agent, it is important to consider the autonomic ramifications of the therapy. Direct vasodilators including short-acting calcium channel blockers (CCBs), particularly dihydropyridines such as nifedipine, cause a rapid decrease in blood pressure and a reflex increase in sympathetic activation, which may be associated with adverse cardiovascular outcomes.69, 70 Some studies

PSYCHOSOCIAL FACTORS

Psychosocial factors (like depression, anxiety, hostility, and social isolation) increase CHD risk both by their association with high-risk behaviors, such as smoking, and by direct pathophysiologic mechanisms, including activation of the sympathetic nervous system.⁸⁵ Depression has been associated with elevated resting heart rate,⁸⁶ decreased heart rate variability,⁸⁷ impaired vagal control,⁸⁸ and elevated levels of plasma norepinephrine,⁸⁹ suggesting chronic inappropriate activation of the

EXERCISE

Interventions for improving autonomic function are listed in Table 3. In today's world, sympathetic activation usually occurs in response to emotional stress, but our body prepares as if it were responding to a physical threat. Increased sympathetic tone that occurs with exercise is physiologic and facilitates increased capacity for physical work. After exertion, sympathetic tone is decreased from baseline, and vagal tone is augmented.¹⁰⁸ This “relaxation response” does not occur after anxiety

OMEGA-3 FATTY ACIDS

The cardiovascular benefits of omega-3 fatty acids, principally docosahexaenoic acid and eicosapentaenoic acid, appear to be mediated by a reduction in the risk of sudden cardiac death.¹¹⁷ Several clinical trials have shown improved outcomes in patients with higher intakes of omega-3 (from dietary intake and supplements).118, 119 The Mediterranean diet appears to protect against cardiovascular disease. In prospective studies, the benefits of this diet are specifically correlated with high

CONCLUSION

Autonomic dysfunction, as measured by resting and peak exercise heart rate, heart rate recovery after exercise, and heart rate variability, is a prevalent and potent CHD risk factor. Therefore, we urge clinicians to develop an increased awareness of the effects of various therapies on autonomic function; consider carefully the risks involved before prescribing medications with sympathomimetic effects, especially in patients with cardiovascular disease; and place greater emphasis on

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ReviewAutonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight

Section snippets

AUTONOMIC DYSFUNCTION AS A RISK FACTOR

HOW AUTONOMIC IMBALANCE INCREASES RISK

INSULIN RESISTANCE AND AUTONOMIC DYSFUNCTION

RISKS OF SYMPATHOMIMETIC DRUGS

β-AGONIST BRONCHODILATORS

LESSONS LEARNED FROM CONGESTIVE HEART FAILURE

CHOICE OF AGENTS FOR HYPERTENSION

PSYCHOSOCIAL FACTORS

EXERCISE

OMEGA-3 FATTY ACIDS

CONCLUSION

Am Heart J

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

Am Heart J

Am Heart J

Am Heart J

J Am Coll Cardiol

Am J Cardiol

Mayo Clin Proc

Am J Cardiol

Am J Cardiol

J Allergy Clin Immunol

Lancet

Chest

Lancet

J Nucl Cardiol

Am J Hypertens

Lancet

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Biol Psychiatry

Am J Cardiol

Am Heart J

Am J Cardiol

Significance of reduction in heart rate in cardiovascular disease

Clin Cardiol

Prognostic significance of the initial electrocardiogram in patients with acute myocardial infarction

JAMA

Impaired chronotropic response to exercise stress testing as a predictor of mortality

JAMA

Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG

JAMA

Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort

Ann Intern Med

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

Heart rate variability and progression of coronary atherosclerosis

Arterioscler Thromb Vasc Biol

Reduced heart rate variability and mortality risk in an elderly cohort: the Framingham Heart Study

Circulation

Impact of reduced heart rate variability on risk for cardiac events: the Framingham Heart Study

Circulation

Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction

Lancet

Cardiovascular neural regulation during and after prolonged high altitude exposure

Eur Heart J

Autonomic nervous control of heart rate at altitude (5050 m)

Eur J Appl Physiol Occup Physiol

Effects of a residential exercise training on baroreflex sensitivity and heart rate variability in patients with coronary artery disease: a randomized, controlled study

Circulation

Weekly variation of acute myocardial infarction: increased Monday risk in the working population

Circulation

Propranolol and the morning increase in sudden cardiac death: the beta-Blocker Heart Attack Trial experience

Am J Cardiol

Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials

Circulation

Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery

N Engl J Med

The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery

N Engl J Med

Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: main results from the β-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS)

Circulation

Mechanisms responsible for sympathetic activation by cigarette smoking in humans

Circulation

Review
Autonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight