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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.
Evolutionary pressures over millions of years have adapted the sympathetic nervous system as a major mediator of the fight or flight response. Adrenergic neurohumoral activation increases heart rate, blood pressure, and cardiac output and dilates large muscular arteries and the bronchioles. These changes are meant to prepare humans for physical confrontation or to respond to acute hemodynamic collapse or respiratory compromise. When the sympathetic nervous system is used in these settings, it improves a person's chance of survival and increases the likelihood that his or her genes will be passed on to the next generation.
Appropriate and intermittent stimulation of the sympathetic nervous system produces immediate improvement in various symptoms, from the mundane (fatigue, weakness, nasal congestion, etc) to the more serious (bronchial constriction, hypotension, and shock). Additionally, some of the exhilaration of life is mediated by adrenergic stimulation, commonly referred to as an adrenaline rush. Conversely, a reduction in sympathetic neurotransmitters such as dopamine and norepinephrine in the brain can produce dysphoria and lethargy. These factors have encouraged the liberal use of sympathomimetics for long-term therapy, ranging from prescription and over-the-counter drugs to “natural” supplements to illicit or illegal drugs. Although these agents produce short-term beneficial effects in many acute situations, long-term use not only results in tachyphylaxis but also exacts a toll on the integrity of the cardiovascular system.
The status of the autonomic nervous system, although often ignored by clinicians, is a major determinant of cardiovascular health and prognosis. Any therapy that chronically activates the sympathetic nervous system and/or diminishes parasympathetic (vagal) tone will increase the risk of cardiovascular events. In contrast, therapies that tip the autonomic balance toward parasympathetic dominance and decrease sympathetic tone will improve prognosis. This simple axiom explains many observations and should be used as a guide in clinical decision making in the diagnosis and treatment of cardiovascular disease. In this article, we review the relationship between autonomic tone and cardiovascular risk and suggest strategies for recognizing and treating this risk factor.
AUTONOMIC DYSFUNCTION AS A RISK FACTOR
Many studies have established an elevated resting heart rate as a risk factor for cardiovascular disease and mortality.
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 extensiveness of Q waves or ST-segment deviation.
Other indicators of the health of the autonomic system can be detected on a routine exercise tolerance test. An impaired chronotropic response to exercise is defined as a failure to achieve 85% of the age-predicted maximal heart rate. This abnormality is present in 11% to 26% of healthy middle-aged adults and increases mortality independent of findings on stress nuclear myocardial perfusion images and coronary angiography.
Heart rate recovery after exercise, which is mediated primarily by vagal tone, has also been shown to be a significant prognostic factor. In a study of 9500 people, Nishime et al
showed that failure to decrease heart rate by more than 12 beats/min during the first minute after exercise (noted in 20% of apparently healthy middle-aged adults) increased mortality 4-fold over the ensuing 5 years (Figure 1). Another large study reported a relative risk of mortality of 2.58 in one third of 5200 healthy adults who had an abnormal heart rate recovery on a screening treadmill test.
Figure 1The 5-year Kaplan-Meier survival estimates in 9454 patients according to deciles of heart rate recovery 1 minute after exercise. Mortality was predicted by abnormal heart rate recovery, hazard ratio of 4.16 (95% confidence interval, 3.33-5.19; P<.001). Reprinted with permission from Nishime et al.
Intact heart rate variability (beat-to-beat variability mediated by a dynamic autonomic nervous system, especially vagal tone) and baroreflex sensitivity (reflex-mediated changes in heart rate as a response to fluctuations in preload and venous return, such as those noted during postural changes) are characteristics of a healthy autonomic system 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,
Fractal analysis of heart rate dynamics as a predictor of mortality in patients with depressed left ventricular function after acute myocardial infarction.
The ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) study showed that both heart rate variability and baroreflex sensitivity were independent predictors of cardiovascular mortality.
Figure 2Fractal analysis with use of the a-variable documented heart rate variability as a powerful predictor of all-cause mortality in 159 patients with depressed left ventricular function after acute myocardial infarction. Impaired heart rate variability (a<.85) was associated with a relative risk of 3.17 (P<.001). Reprinted with permission from Mäkikallio et al.
Fractal analysis of heart rate dynamics as a predictor of mortality in patients with depressed left ventricular function after acute myocardial infarction.
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 heart rate of greater than 180 beats/min, and a brisk heart rate recovery within the first minute of resting. Within the days to weeks that climbers are acclimating to progressively higher altitudes, their resting heart rate gradually increases, peak exercise heart rate decreases, and heart rate recovery becomes delayed.
Altitudes greater than 26,000 feet are termed the death zone. As climbers ascend above this level, their resting heart rate typically increases to 120 to 140 beats/ min, and their peak exercise heart rate decreases to this same level; thus, their heart rate recovery is nonexistent. Essentially, climbers are dying of hypoxia and exposure, and the sympathetic nervous system, while trying to compensate, is becoming less and less effective because of down-regulation of the adrenergic receptors in the face of continuous maximal sympathetic stimulation. These same adaptations, although less extreme, operate under normal ambient conditions.
Excessive sympathetic stimulation and diminished vagal tone not only are markers of an unhealthy cardiovascular system but also in part cause the adverse events. Chronic sympathetic hyperactivity increases the cardiovascular workload and hemodynamic stresses and predisposes to endothelial dysfunction, coronary spasm, left ventricular (LV) hypertrophy, and serious dysrhythmias.
Effects of a residential exercise training on baroreflex sensitivity and heart rate variability in patients with coronary artery disease: a randomized, controlled study.
The risks of MI, sudden cardiac death, and stroke are highest during the first few hours after awakening in the morning, correlating with the circadian peak in sympathetic activity.
In the setting of LV dysfunction, abnormal autonomic tone is the most sensitive predictor of cardiac and arrhythmic mortality, even more so than documented ventricular tachycardia.
Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) Investigators
et al.
Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials.
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 coincidence) were wearing a Holter monitor during a major earthquake in Taiwan, 9 showed enhanced sympathetic modulation and/or decreased vagal tone within 30 minutes.
Interestingly, the 3 people who did not show worsening autonomic tone were all taking a β -blocker at the time of the earthquake.
In animal models, β -blockers decrease both stress-induced and diet-induced atherosclerosis. Recently, in a 3-year randomized placebo-controlled trial involving 793 patients, low-dose metoprolol (25 mg/d) reduced progression of carotid atherosclerosis as effective as a statin.
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).
Clearly, autonomic imbalance is much more than a surrogate marker of increased CHD risk.
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.
Diabetes and the metabolic syndrome (hypertension, insulin resistance, obesity, and atherogenic dyslipidemia) adversely affect cardiac autonomic function and are associated with increased risk of cardiovascular events.
; the insulin resistance syndrome also predisposes to cardiovascular hyper-responsiveness to sympathetic stimulation and has been shown to reduce heart rate variability.
A recent study showed that glucose intolerance was the strongest determinant of cardiovascular autonomic imbalance compared to the other standard risk factors.
Symptomatic autonomic neuropathy is common in patients with long-standing poorly controlled diabetes and is associated with increased 5-year mortality.
However, chronic hyperinsulinemia, even in the absence of type 2 diabetes mellitus, is associated with heightened sympathetic tone and decreased vagal tone.
Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects.
Data from the Framingham Heart Study recently confirmed that diabetes and impaired fasting glucose levels are associated with reduced heart rate variability.
Although β-blockers tend to worsen insulin sensitivity, they decrease mortality in diabetic patients partially by improving the autonomic imbalance and risk of sudden death.
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).
Legal sympathomimetic medications are widely used for various conditions, including weight loss, allergy or sinus problems, asthma, and chronic lung disease. Sympathomimetic agents are often found in over-the-counter products, including herbal preparations, and are frequently taken in combination with other stimulants and without supervision.
Two recently published studies (released early because of public health implications) renewed concerns about the safety of nonprescription sympathomimetic medications. In the first study, phenylpropanolamine (PPA), often used as a decongestant or appetite suppressant, was found to increase the risk of hemorrhagic stroke in women.
As a result, the Food and Drug Administration recommended that products containing PPA be removed voluntarily from the market. In a related study, ephedra alkaloids, found in herbal preparations like ma huang or Metabolife and used frequently for weight loss, were found to be associated with various adverse cardiovascular and central nervous system effects, including hypertension, stroke, and MI.
The National Football League recently banned ephedra use because 4 players died in summer 2001 training camps; 3 had ephedra in their bloodstream, and 1 had an ephedra-containing drink in his locker.
Although a relationship between ephedra use and death was not proved in all cases, the National Football League policy was intended to protect the health of players until further study could be undertaken.
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, supplements containing ephedra accounted for 42% of all the reported adverse events related to nutritional supplements during that period.
β-Agonists are used frequently in the setting of an acute upper respiratory tract infection, which has been independently associated with an increased risk of MI.
A recent case-control study showed that the use of inhaled β-agonists was associated with an increased risk of MI (adjusted odds ratio, 1.67; 95% confidence interval, 1.07-2.60) in patients with known cardiovascular disease.
Patients with chronic lung disease often use a β-agonist (albuterol) and an anticholinergic medication (ipratropium) concurrently. Anticholinergic medications can increase heart rate and decrease heart variability.
A case-control study showed that, in patients with asthma, cardiovascular deaths were more common among those prescribed ipratropium at discharge (odds ratio, 3.55; 95% confidence interval, 1.05-11.94).
A wide variety of medications have anticholinergic effects, and caution is advised when sympathomimetic and anticholinergic medications are used together.
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, from dopamine and dobutamine decades ago to more recent designer inotropes with associated vasodilatation like milrinone or vesnarinone, 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).
recently reported that use of sympathomimetic drugs increased the risk of hospitalization for arrhythmias in patients with CHF.
Figure 3The Prospective Randomized Milrinone Survival Evaluation (PROMISE) randomized 1088 patients with congestive heart failure (CHF) (class III or IV) to oral milrinone or placebo. All-cause mortality was 28% higher in the patients taking milrinone and 53% higher among those with class IV CHF (95% confidence interval, 13%-107%; P=.006). Reprinted with permission from Packer et al.
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, uncontrolled 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, dysrhythmias, apoptosis, and progressive LV dysfunction.
Multiple studies have unequivocally documented that β -blockers are effective for improving outcomes in patients with CHF and LV dysfunction. These benefits have been found with carvedilol,
Because of the counterintuitive nature of the use of a β -blocker for the failing heart and the transient worsening of symptoms after initiation of therapy, many practicing physicians have been slow to embrace this life-saving therapy. Although β -blockers are the most important therapy for normalizing the prognosis of CHF, they are currently used in fewer than 1 in 5 eligible patients nationwide.
CHOICE OF AGENTS FOR HYPERTENSION
Sympathetic activity has been shown to be a factor in the development of hypertension.
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.
Some studies have indicated that patients treated with a short-acting CCB are at increased risk for MI and have a higher mortality rate than patients treated with other types of medications.
Peripheral β -blockers (doxazosin, terazosin) lower blood pressure via peripheral vasodilation but activate the central sympathetic nervous system. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), doxazosin was found to increase the risk of CHF and stroke compared to a diuretic.
ALLHAT Collaborative Research Group Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
Drugs that normalize sympathetic hyperactivity, like β-blockers and angiotensin-converting enzyme (ACE) inhibitors, not only lower blood pressure but also reduce the risk of adverse cardiovascular events beyond what would be predicted based on the improvement in hypertension alone.
Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction: a meta-analysis of randomized clinical trials.
Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy.
β -Blockers lower heart rate and restore normal β-receptor responsiveness, improving peak exercise heart rate, heart rate recovery, and beat-to-beat variability. β-Blockers have also been shown to reduce the risk of sudden cardiac death by 30% to 50%
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.
suggesting chronic inappropriate activation of the sympathetic nervous system. All 11 prospective studies evaluating a possible link between major depression and CHD showed positive results.
Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease: systematic review of prospective cohort studies.
A history of major depression is a potent independent predictor for the future risk of CHD events, with an odds ratio of approximately 6.0, placing it among the strongest of cardiovascular risk factors.
and CHD. Additionally, lack of social support disturbs normal autonomic tone and is associated with increased risk of cardiovascular events, in both healthy populations and those with known CHD.
An exaggerated heart rate and blood pressure response to stressful situations, labeled the hot responder trait, has been linked to an increased risk of cardiac events.
Exaggerated blood pressure responses during mental stress are associated with enhanced carotid atherosclerosis in middle-aged Finnish men: findings from the Kuopio Ischemic Heart Disease Study.
and other forms of social connection, such as dog ownership, have been associated with activation of the para-sympathetic nervous system and decreased risk of future cardiovascular events. Interventions that have used psychosocial support programs for patients with CHD have shown mixed results, but some studies have shown benefit.
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.
Although nonphysiologic stresses increase the risk of adverse cardiovascular events, normal physiologic sympathetic activation (eg, during exercise or sexual activity) improves physical conditioning, mood, and cardiovascular prognosis. Exercise transiently stimulates the sympathetic nervous system, but because it strongly augments background vagal activity, it is an effective and practical means to restore a healthy balance of autonomic tone.
The sympathetic activation that occurs during exercise can trigger sudden death or acute MI, predominantly in sedentary persons and especially during extreme exertion.
Thus, exercise has been referred to as a two-edged sword, increasing risk in the short term in susceptible persons, while reducing chronic risk in regular exercisers.
Effects of a residential exercise training on baroreflex sensitivity and heart rate variability in patients with coronary artery disease: a randomized, controlled study.
Frequent physical activity reduces sympathetic activity through many indirect mechanisms, including weight loss, reduced anxiety and depression, improved insulin sensitivity, and as an aid in smoking cessation efforts.
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.
Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study.
The Mediterranean diet appears to protect against cardiovascular disease. In prospective studies, the benefits of this diet are specifically correlated with high omega-3 content, and cardiovascular outcomes are improved predominantly by preventing sudden cardiac death.
Several studies suggest that omega-3 fatty acids (especially docosahexaenoic acid) may improve parameters of autonomic function, including baroreflex sensitivity and heart rate variability.
Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction.
However, routine use of omega-3 fatty acids for this indication should be deferred until further prospective randomized trials are completed.
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 interventions (like regular, moderate-intensity exercise, β-blockers, and ACE inhibitors) that have been shown to improve autonomic function and outcomes in patients with CHD.
REFERENCES
Gillman MW
Kannel WB
Belanger A
D'Agostino RB
Influence of heart rate on mortality among persons with hypertension: the Framingham Study.
Fractal analysis of heart rate dynamics as a predictor of mortality in patients with depressed left ventricular function after acute myocardial infarction.
Effects of a residential exercise training on baroreflex sensitivity and heart rate variability in patients with coronary artery disease: a randomized, controlled study.
Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) Investigators
et al.
Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials.
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).
Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects.
Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction: a meta-analysis of randomized clinical trials.
Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy.
Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease: systematic review of prospective cohort studies.
Exaggerated blood pressure responses during mental stress are associated with enhanced carotid atherosclerosis in middle-aged Finnish men: findings from the Kuopio Ischemic Heart Disease Study.
Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study.
Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction.
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