Beneficial Effects of Physical Activity on Baroreflex Control in the Elderly

Abstract

The baroreflex mechanisms, by controlling autonomic outflow to the heart and circulation, contribute importantly to neural circulatory control. The main function of the baroreflex is to prevent wide fluctuations in arterial blood pressure and to maintain the physiological homeostasis under basal resting conditions and in response to acute stress. Baroreflex‐mediated changes in autonomic outflow affect heart rate, myocardial contractility, and peripheral vascular resistance. The baroreflex control of heart rate is of particular interest in pathological conditions, since it has been associated with increased propensity for cardiac mortality and sudden death. Aging is associated with significant cardiovascular modifications. The changes in baroreflex function that occur with age have been systematically studied by several methodological approaches. The available evidence indicates a reduced arterial baroreflex control of heart rate favoring an increase in sympathetic and a decrease in parasympathetic drive to the heart as well as an impairment in the baroreceptor control of blood pressure. Both kinds of changes have resultant clinical implications. Exercise training can modulate the age‐related decline in baroreflex function and the attending abnormalities in autonomic control, thus accounting for some of the beneficial effects of physical activity in reducing the risk of cardiovascular morbidity and mortality.

The arterial baroreceptors play a major role in controlling the activity of cardiac autonomic nerves, thereby participating in the regulation of the cardiovascular system in the adaptation to both, various activities in health and several manifestations of cardiac disease. In a simplified paradigm, by baroreceptor stimulation, arterial pressure changes can modulate both sympathetic and vagal activity and, as a consequence, heart rate, myocardial contractility, and systemic vascular resistance.

The normal aging process causes modifications in the autonomic control of the cardiovascular system. The degenerative process that affects baroreflex function with age is characterized by a reduced arterial baroreflex control of heart rate favoring heightened cardiac sympathetic tone with parasympathetic withdrawal and a decreased ability of the baroreflexes to buffer changes in systemic blood pressure.

Regular physical activity is known to prevent or even to improve the age‐related abnormalities of cardiac autonomic function.

This article will review: (a) the physiological basis for the arterial baroreflex control, (b) the mechanisms underlying the impairment in the baroreflex control with age, and (c) the role of exercise in preventing or improving the age‐related abnormalities in baroreflex function.

THE ARTERIAL BARORECEPTOR REFLEX

The mechanisms of arterial baroreflex control in humans both in health and disease have recently been extensively reviewed.1

Arterial baroreceptors are stretch receptors and are mainly located in the wall of the carotid sinus and in the wall of the aortic arch. Baroreceptor nerve endings are sensitive to the mechanical deformation of the vessel wall and change their rate of firing with changes in transmural pressure. Firing from baroreceptors show a threshold pressure, below which no response occurs, an operating range and a saturation level. Several factors, including circulating catecholamines, endothelial‐dependent factors and neural NO release, can modulate baroreceptor responses at the peripheral level by increasing or decreasing the sensitivity of the arterial baroreceptors.

Afferent fibers carrying sensory information from carotid and aortic baroreceptors join the glossopharyngeal and vagus nerves to travel to the brain stem where they form the first synapse within the confines of the nucleus of the tractus solitarius. The second‐order neurons from the nucleus of the tractus solitarius project to a number of structures including the dorsal motor nucleus of the vagus and the nucleus ambiguous where reside the parasympathetic preganglionic neurons and the rostral, caudal, and ventrolateral medulla where is located the main premotor nucleus for cardiovascular sympathetic outflow. Projections from the nucleus of the tractus solitarius have also been traced to the lateral reticular formation and hypothalamus. Efferent vagal fibers run in the vagus nerve to the heart where they synapse in the cardiac ganglia. The preganglionic neurons of the sympathetic nerves are in the intermediolateral cell column of the spinal cord and project to postganglionic neurons located primarily in the stellate ganglia.

The baroreflex control of circulatory homeostasis occurs on a negative feedback basis. Activation of arterial baroreceptors by a rise in systemic arterial pressure leads to an increased discharge of vagal cardioinhibitory neurons and a decreased discharge of sympathetic neurons which results in bradycardia, decreased cardiac contractility and decreased peripheral vascular resistance, and venous return with the aim of buffering the arterial pressure change.2, 3 Conversely, a decrease in systemic arterial pressure through a decrease in the baroreceptor firing rate results in sympathoexcitation and parasympathetic withdrawal, leading to tachycardia and increase of cardiac contractility, vascular resistance, and venous return. Because reflex sympathetic responses are slower than vagal ones,4 the fastest baroreflex control involves changes in heart rate that are solely vagally mediated. Although a direct negative inotropic action of the vagus has long been a matter of debate, by the use of pulsed aortic Doppler velocimetry to assess beat‐by‐beat changes in stroke volume, Casadei et al.5 were able to prove that the rapid reduction in cardiac output that follows the activation of the arterial baroreflex is mediated by the vagus through a simultaneous effect on both stroke volume and heart rate.

Arterial baroreflex responses, however, are much more complex then described as they are modulated by the interaction between high brain centers and afferent inputs from multiple reflexogenic areas in the heart, lungs, and in the vessels. One example is represented by the interaction between the baroreceptor reflex and respiratory activity that contributes to the origin of respiratory sinus arrhythmia. Firing in the cardiac vagal efferent fibers is enhanced in the expiratory phase of respiration while there is a reduction during the inspiratory phase that is associated with tachycardia. This autonomic modulation is mediated both by the direct effect of the oscillatory activity of the respiratory centers and by reflex activity from the lungs and from arterial baroreceptors which are sensitive to respiratory‐related changes in stroke volume and cardiac output.

Under normal circumstances and when arterial pressure is normal, there is a prevailing level of arterial baroreceptor discharge so that vagal efferent activity is tonically excited and sympathetic activity is tonically inhibited. During circumstances such as exercise, vagal activity is low and circulatory control is mediated principally by sympathetic mechanisms. Abnormalities in baroreceptor mechanisms occurring in a variety of pathological conditions could compromise their tonic restraining influence on the heart and circulation leading to sympathoexcitation and parasympathetic withdrawal.

A spectrum of techniques has been developed to evaluate arterial baroreflex control mechanisms in humans.6 A widely used method to quantify the sensitivity of the arterial baroreflex involves the intravenous administration of vasoactive drugs that would alter the degree of baroreceptor activity. Baroreflex sensitivity (BRS) is evaluated as the slope of the relationship between prolongation or shortening in RR interval in response to increases or decreases in systolic arterial pressure elicited by the vasoconstrictor (phenylephrine) or the vasodilator (nitroglycerine) drug.7, 8 As the relationship between blood pressure and heart period is sigmoidal, only the linear portion is used for the quantification of BRS. Although vasoactive drugs are used making the assumption to evaluate arterial baroreceptor reflex responses, it is worth note that: (a) they are not completely devoid of direct effects on heart rate and (b) that the pressure stimulus causes a simultaneous activation of multiple reflexogenic areas, particularly cardiopulmonary receptors, which may interfere or even counteract the arterial baroreceptor reflex. However, this lack of selectivity in the response may not be regarded as a limitation when BRS is used as a measure of the net autonomic balance to the heart. The Valsalva maneuver (a natural challenge for the baroreceptors)9 and the neck chamber technique (which provides a selective manipulation of carotid baroreceptors and allows assessing the corresponding blood pressure response)10 represent noninvasive alternatives to vasoactive drugs injection. With all these techniques that imply a “system perturbation,” the difficulty in the quantification of the baroreflex relies in the need to approximate an open‐loop condition in the closed‐loop control system that regulates arterial blood pressure. At variance with the previous methods, the estimates of BRS from spontaneous fluctuations of blood pressure and RR interval—the so‐called “spontaneous BRS”—would partially reflect the gain of the baroreceptors in a closed‐loop system. A variety of computational methods can be applied to the analysis of the interrelationship between RR and arterial pressure variabilities. There are two major approaches: one based on “time domain”11 and the other on “frequency domain” measurements. For spectral methods several algorithms have been developed to calculate the gain of the baroreflex.12, 13, 14 The integrity of the relevant adrenergic and muscarininc receptors at the sinus node level is a common denominator with all these techniques.

At variance with previous techniques where the efferent neural responses to changes of baroreceptor activity are largely inferential, baroreflex control of sympathetic outflow can be directly quantitated by the microneurographic technique that allows direct intraneural recordings of efferent sympathetic nerve activity to both muscle blood vessels (MSNA) and skin blood vessels (SSNA).15 With usual approaches MSNA is analyzed in terms of sympathetic nerve bursts, which are synchronous with blood pressure pulses. Very good correlations between levels of antecubital vein plasma noradrenaline and muscle sympathetic nerve traffic have been found in normal subjects both at baseline16 and during interventions such as infusion of vasoactive drugs.17

EFFECTS OF AGING ON THE BAROREFLEX ARC

Associated with changes in the structure and function, including progressive arterial stiffening, increases in systolic arterial pressure and left ventricular mass, the normal aging process is characterized by several alterations in the autonomic regulation of the cardiovascular system. As a result of cardiovascular instability, orthostatic hypotension and vasovagal syncope are common problems among elderly patients, associated with significant morbidity and mortality.

A vast amount of data has consistently shown that increasing age significantly reduces cardiac parasympathetic nerve activity18 and the cardiovagal baroreflex control of heart rate. Cardiovagal BRS and age are inversely related.19, 20 The decline of BRS with age was first described by Gribbin et al.19 While this study included very few subjects older than 60 years, subsequent data showed that the relation with age is diminished or lost beyond this point, suggesting that the majority of the reduction seen in BRS with age has already occurred by the fifth decade.21, 22

Although a consensus exists that resting sympathetic nervous system activity increases with age, there is no definitive evidence that ageing modifies the sympathetically mediated baroreflex responses. Several studies recording resting MSNA show that sympathetic nerve traffic tends to increase with age.22, 23, 24, 25 A gender‐selective interaction has been found between age and increased resting sympathetic activity. In 120 healthy males and 96 healthy females aged 20 to 72 years, MSNA increased with age in both sexes but the rate of increase in MSNA per decade was 2.5‐fold higher in women that in men.25 Other factors, however, over increased nerve traffic, come into play in determining the increased spillover of norepinephrine from the heart in older subjects.26

The more controversial relationship between age and sympathetic BRS is a likely consequence of different methodological approaches. Moreover, the sympathetic efferent limb is more difficult to evaluate in humans because, at variance with the cardiovagal BRS, the thorough evaluation of sympathetic gain seems to require the combined registration of sympathetic activation to pressure falls and sympathoinhibition to pressure rises.27 With the use of vasoactive drugs, several studies have demonstrated that baroreflex‐mediated sympathetic control of blood vessels is preserved in healthy normotensive adult humans even into the seventh age decade.22, 28, 29 These results would suggest that changes in sympathetic BRS do not contribute to the increase in resting sympathetic activity with age. By contrast, the arterial baroreflex inhibition of MSNA was attenuated during the Valsalva Maneuver in seven aged subjects30 while the opposite was found during hypovolemia produced by lower body negative pressure.31 These stimuli, however, are heterogeneous, unloading cardiopulmonary baroreceptors, as well as differently unloading aortic and carotid baroreceptors. Recent investigations suggest that ageing actually does affect sympathetic responses.32, 33 However, age‐related alterations in baroreflex function are differentially manifested in the reflex response of MSNA to falls and rises in blood pressure: while sympathetic activation to pressure fall decreases with age, sympathoinhibition to pressure rise increases.32 Similar results were found when assessing the magnitude of the changes in blood pressure to simulated carotid hypertension and hypotension obtained by the application of the neck chamber technique. In older subjects, simulated hypotension induced an attenuated pressor response, while an augmented depressor response to simulated hypertension was observed.33

Thus, the age‐related impaired ability of the baroreflexes to buffer blood pressure changes result from the combined effect of reduced cardiac vagal modulation of heart rate (and cardiac output) and chronically elevated sympathetic activity. However, the age‐related functional changes of blood pressure control are a more complex interaction in which the role of an altered responsiveness to vasoactive drugs cannot be disregarded.34

The mechanism of age‐related arterial baroreflex impairment is probably multifactorial and may be located in all components of the reflex (the afferent limb, central processing or the efferent limb). The age‐related arterial stiffening of large arteries in which the baroreceptors are located is a key mechanism. This arterial stiffening by reducing the stretch of baroreceptors may reduce the amount of incoming sensory information for any given change in pressure. Among healthy men, a number of studies have reported that reduced carotid artery compliance was the strongest independent physiological correlate of the age‐associated decrease in cardiovagal BRS.35, 36 However, arterial stiffness is not the only determinant of age‐related baroreflex decline. By the concurrent recording of beat‐to‐beat arterial pressure, R‐R interval and carotid diameter during vasoactive drug administration, Hunt et al.37 were able to separate the mechanical transduction of pressure into barosensory stretch from the neural transduction of stretch into vagal outflow and found that both the mechanical and the neural component of baroreflex contribute to the lower integrated cardiovagal gain in older individuals. The interaction between mechanical and neural components is also an important determinant of the integrated sympathetic baroreflex responses.32

A defect in central nervous system integration of sensory information from baroreceptors also contributes to the impaired baroreflex with aging.38 Esler et al.39 investigated the influence of aging on brain norepinephrine turnover and suggested that forebrain noradrenergic mechanisms controlling sympathetic outflow are activated in aging. A reduced restraining influence from impaired baroreceptors on sympathetic medullary centers cannot, however, be excluded.

The efferent parasympathetic pathways of the baroreflex may also be involved in the process leading to the decreased cardiac vagal activity with age. Some evidence does not support this possibility. By the administration of a cold face test (whose afferent components are mediated through pathways other than the afferent baroreflex pathway) O'Mahony et al.40 did not find any difference in the bradycardic response (vagally mediated) among young and elderly subjects, thus suggesting a major role for a defective afferent rather than efferent component of the baroreflex arc. Alterations in target organ responses should also be taken into account when considering the overall effects of changes in vagal outflow to the heart. Changes in muscarinic receptors and their responsiveness could also contribute to the depressed BRS in aging. In right atrial appendages (from patients aged 5 days to 76 years), it was found that the density of M₂‐cholinoceptor decreased with age and aged volunteers showed a decrease in the inhibitory effect of low‐dose pirenzepine on isoprenaline‐stimualted heart rate.41

As a consequence of age‐related arterial baroreflex impairment, changes in the sympathovagal balance to the heart may have a number of important physiological and pathophysiological effects for health and disease. In elderly individuals, reduced vagal control of the heart relates to increased cardiac and cerebrovascular mortality, independent of classical risk factors.42

Since the early 1970s, some experimental studies yielded important insights into the pathophysiological implications of heart disease‐related baroreflex impairment. It was recognized that cardiac electrical stability can be affected by changes in autonomic flow43, 44 and that baroreceptors reflexes can be modulated by cardiac afferent sympathetic activity activated by mechanical and chemical stimuli.45 In addition, it was demonstrated the importance of adequate baroreceptor activity to respond to the hemodynamic challenge of ventricular tachycardia.46 An animal model provided the first evidence that reduction in cardiac parasympathetic control is associated with an increased risk for sudden death. In this canine model, BRS, as measured by reflex heart rate response to pharmacologically induced elevation of arterial pressure, was impaired by myocardial infarction, with the greatest impairment noted in animals particularly susceptible to sudden death.47

Similarly in humans, a tight relationship between reduced BRS and the most advanced disease state was first reported by Eckberg et al.48 and was subsequently found to be associated with an increased risk of cardiac mortality and sudden cardiac death in postmyocardial infarction and heart failure patients.49, 50, 51 Advanced age decreases, but does not eliminate the value of a reduced cardiovagal BRS in predicting poor outcome52 supporting the view that further age‐associated changes in BRS could exaggerate the risk of death in the elderly.

Age, per se, is a major risk factor and contributor to all cardiovascular morbidities and mortality. It is tempting to speculate that the age‐related autonomic dysfunction may magnify the effects of concomitant cardiovascular disease and that interventions targeted to improve the autonomic balance might be associated with a reduction in the risk of cardiovascular disease and death.

ROLE OF EXERCISE IN PREVENTING THE AGE‐RELATED ABNORMALITIES IN BAROREFLEX FUNCTION

The importance of adequate exercise in maintaining cardiovascular health and preventing disease is extraordinarily well established.53 Aerobic capacity has emerged as an independent predictor of health outcomes in the general population and in diseased patients. In epidemiological studies, a low level of aerobic capacity (bottom 20%) carried an increased risk for all‐cause and cardiovascular mortality after adjustment for age, gender, cardiovascular disease, and conventional risk factors54, 55, 56 indicating that improving exercise capacity can reduce the risk of all‐cause and cardiovascular mortality.

Among the myriad of beneficial effects of exercise across all the body's physiological functions, there is no doubt that some of the protective effects of exercise are largely due to its impact on the autonomic nervous system. In the nurse's health study, only ∼59% of the risk reduction for all forms of cardiovascular disease could be attributed to the effects of exercise on traditional risk factors.57 Autonomic dysfunction is in fact the missing risk factor that is positively altered by exercise. The beneficial effects of exercise on the autonomic nervous system have been regarded to explain, at lest in part, the “risk factor gap” associated with exercise and physical activity.58

Exercise training can keep the autonomic nervous system healthy. One of the most striking effects of exercise training on the cardiovascular system is the presence of resting bradycardia, together with a less‐marked but significant reduction in mean arterial pressure.

Both cross‐sectional and longitudinal studies have investigated the effects of exercise training in healthy sedentary subjects and in athletes. Physically fit individuals have a lower resting heart rate,59 a greater resting cardiac vagal tone,60 and a faster heart rate recovery postexercise.61 In healthy sedentary subjects, Grassi et al.62 showed that in resting conditions and during loading manipulations, endurance training markedly lowered sympathetic nerve traffic, investigated by microneurography, and baroreceptor sympathetic reflex sensitivity.

The influence of autonomic nervous system activity in generating a training‐induced bradycardia has been examined during pharmacological cardiac autonomic blockade.63, 64 Collectively, these studies reported an increased parasympathetic and a reduced sympathetic control of heart rate following endurance training of proper duration and intensity. These training‐induced autonomic changes, coupled with a possible reduction in intrinsic heart rate, decrease resting heart rate.

A change in BRS is a relevant mechanism underpinning the training‐induced autonomic changes. Cross‐sectional studies suggest that age‐related declines in baroreflex function may be prevented by habitual physical activity.31, 36, 37, 65 Aerobic exercise, even of moderate intensity, appears to be a sufficient stimulus to attenuate the age‐associated decline in cardiovagal BRS in healthy men.64, 65 Moreover, regular aerobic exercise can increase cardiovagal BRS in previously sedentary middle‐aged and older men.65 Several mechanisms can contribute to improve BRS including enhanced arterial compliance, augmented muscarinic receptor density, or central integration of afferent sensory information. Indeed, changes in some groups of neurons involved in sympathetic regulation have been shown as a result of central nervous system plasticity due to chronic exercise.66

A depressed BRS with the attending autonomic dysfunction characterized by reduced parasympathetic and increased sympathetic activity is common in many cardiovascular disease states and is related to a higher incidence of morbidity and mortality.49, 50, 51 A significant reduction in cardiac death as well as in morbidity and disability has been reported for patients in multifactorial intervention programs that included exercise training.67, 68

There is now convincing evidence that some of the protective and therapeutic effects of chronic exercise training are related to the impact on the autonomic nervous system and on baroreflex function. At the experimental level, increases in cardiac parasympathetic activity with aerobic training were found to exert a protective effect against life‐threatening arrhythmia.69 In dogs with a healed myocardial infarction, a 6‐week daily exercise program on a treadmill could protect against ventricular fibrillation induced by acute myocardial ischemia in those animals previously shown to be susceptible to sudden cardiac death. In contrast, the animals that had been kept resting in a cage were not protected.69 In a rat model of myocardial infarction and diabetes, the BRS improvement in trained animals resulted in a reduction of mortality compared with sedentary animals.70 Several investigators found that physical training increased parasympathetic activity in patients with coronary artery disease and heart failure.71, 72, 73, 74, 75 However, very limited data have been provided linking the improvement in baroreflex function following exercise training and improved survival. One such study was performed in 95 patients with a recent MI73 who were randomly assigned to a 4‐week endurance training period or to no training. After 4 weeks, BRS improved by 26% (P = 0.04) in trained patients, whereas it did not change in nontrained patients. The group of patients that exhibited the greatest change in BRS exhibited the lowest mortality during a 10‐year follow‐up whereas more than 20% of the patients with smaller changes in BRS died during the follow‐up period, suggesting that exercise training is associated with increased survival only in conjunction with an adequate modulation of the autonomic balance toward increase in vagal activity, as revealed by the increase in BRS.

SUMMARY

A preserved baroreceptor function is a marker of cardiovascular well‐being. The age‐related decline in the effectiveness of baroreceptor mechanisms in controlling autonomic outflow to the heart and circulation is a predisposing factor for the development of cardiovascular diseases. Exercise training, even of moderate intensity, is highly protective against age‐associated baroreflex dysfunction. The beneficial effects of physical activity to health and well‐being can be ascribed—to a large extent—to the preservation of baroreceptor activity and cardiac autonomic function.