Vol. 283, Issue 4, R815-R826, October 2002
INVITED REVIEW
Arterial baroreflex function and cardiovascular variability:
interactions and implications
Paola A.
Lanfranchi and
Virend K
Somers
Division of Hypertension and Division of Cardiovascular
Diseases, Mayo Clinic, Rochester, Minnesota 55905
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ABSTRACT |
The arterial baroreflex
contributes importantly to the short-term regulation of blood pressure
and cardiovascular variability. A number of factors (including reflex,
humoral, behavioral, and environmental) may influence gain and
effectiveness of the baroreflex, as well as cardiovascular variability.
Many central neural structures are also involved in the regulation of
the cardiovascular system and contribute to the integrity of the
baroreflex. Consequently, brain injuries or ischemia may induce
baroreflex impairment and deranged cardiovascular variability.
Baroreflex dysfunction and deranged cardiovascular variability are also
common findings in cardiovascular disease. A blunted baroreflex gain
and impaired heart rate variability are predictive of poor outcome in
patients with heart failure and myocardial infarction and may represent an early index of autonomic activation in left ventricular dysfunction. The mechanisms mediating these relationships are not well understood and may in part be the result of cardiac structural changes and/or altered central neural processing of baroreflex signals.
baroreflex; autonomic nervous system
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INTRODUCTION |
THE BAROREFLEXES CONTRIBUTE
importantly to neural circulatory control. Abnormalities in arterial
baroreflex function have been linked to derangements in cardiovascular
variability and to adverse cardiovascular outcomes. This overview will
examine the physiology of the arterial baroreflex, methods of measuring baroreflex gain, and physiological and pathologic conditions that alter
baroreflex function. We will also address how baroreflex function may
alter cardiovascular variability and vice versa, addressing in addition
nonneural effects of impaired baroreflex function. Last, we will
evaluate the interaction between measurements of baroreflex gain,
cardiovascular variability, and cardiovascular disease, examining
the possibility that changes in central neural processing may
contribute to the link between baroreflex dysfunction, impaired
variability, and cardiovascular pathology.
We sought to focus primarily on more recent novel insights. The
literature on the physiological and pathologic aspects of baroreflex
function, cardiovascular variability, and cardiovascular disease is
vast. We are, therefore, unable to reference the majority of papers in
the field, but have cited a number of preceding reviews, which
encompass many of the omitted references.
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PHYSIOLOGY OF THE BAROREFLEX AND METHODS TO EXPLORE ITS FUNCTION |
Physiological aspects of baroreflex.
The arterial baroreflex seeks to regulate the absolute
blood pressure and ultimately to maintain circulation to the brain and
other organs (107). Baroreceptors sense systemic blood
pressure indirectly, by the extent of stretch of receptors in the walls of the carotid arteries and of the aorta. Changes in arterial baroreceptor afferent discharge transmitted to the central nervous system trigger reflex adjustments that buffer or oppose the changes in
blood pressure: a rise in pressure elicits reflex parasympathetic activation and sympathetic inhibition, with subsequent decreases in
heart rate (HR), cardiac contractility, vascular resistance, and venous
return (88). Conversely, a decrease in arterial pressure reduces baroreceptor afferent discharge and triggers reflex increases in HR, cardiac contractility, vascular resistance, and increased venous
return. Thus the baroreflex, by affecting blood pressure and HR
control, provides powerful beat-to-beat negative feedback regulation of
arterial blood pressure that minimizes short-term fluctuations in
pressure. However, the arterial baroreflex may not be the only feedback
mechanism involved in acute blood pressure control. Endogenous nitric
oxide constitutes a second system, which, by acting also through a
feedback mechanism, is involved in the short-term regulation of blood
pressure (45, 77). Stimulated by the shear stress induced
by increases in arterial pressure, this potent vasodilator response is
rapidly effective in counteracting the initial rise in blood pressure
(77).
Methods of measurement.
One index of baroreflex "health" is the degree of change in heart
rate or sympathetic traffic for a given unit change in blood pressure
(for review, see Ref. 92). This may be quantified as the
response of the cardiovascular system to the application of an external
stimulus, mechanical (94) or pharmacological
(56), in standardized laboratory conditions. An
alternative in vivo approach evaluates spontaneous baroreflex
modulation of heart rate in a daily life setting by identifying
sequences of consecutive beats in which progressive increases in
systolic blood pressure (SBP) are followed by a progressive lengthening
in pulse interval (or vice versa) (7). The slope of the
regression line between SBP and pulse intervals within these sequences
is taken as the magnitude of the reflex gain. A third method to assess
baroreflex function is provided by cross-spectral analysis of short
segments of SBP and R-R or peripheral sympathetic nerve activity to
muscle (MSNA). This approach relies on the assumption that a certain frequency band of HR variability, between 0.04 and 0.35 Hz
(18), is modulated by the baroreflex. This construct is
based on the coherent relationship between SBP and R-R (or MSNA), each
of which oscillate at the same frequency in the power spectrum
(2, 13, 85). Baroreflex sensitivity is expressed by the
gain of the transfer function relating changes in blood pressure to
coherent changes in R-R or MSNA (2, 87, 99).
All these methods for computing baroreflex gain assume linearity of the
relationship between changes in blood pressure and R-R or MSNA. Simple
mathematical models indicate that there is a strong linear coupling
between arterial blood pressure and sympathetic nerve activity and/or
R-R interval (9, 21). However, there is emerging evidence
that the R-R and MSNA responses to blood pressure may be modulated in
accordance with nonlinear dynamics (97).
Neural and nonneural mechanisms modulating baroreflex function.
Any interpretation of in vivo measurements of HR variability and
baroreflex gain must acknowledge the influences of respiration, other
reflexes, and central neural mechanisms.
Respiration modulates the influence of the baroreflex on cardiac vagal
motoneurons: inspiration decreases and expiration enhances the cardiac
vagal responses to baroreflex activation (22).
Hyperventilation impairs baroreflex modulation of HR and sympathetic
nerve traffic (115). A change in respiratory pattern, for
example during resistive load breathing, may itself affect respiratory
sinus arrhythmia, independent of the arterial pressure changes
accompanying respiration (11).
Other mechanisms, of reflex or central origin, may contribute to
coherent R-R-SBP variabilities independent of the baroreflex pathways.
Low-pressure receptors activated by respiration-related changes in
blood volume and central venous pressure may induce changes in R-R
independent of SBP. These R-R changes in turn elicit SBP variation
through the Frank-Starling mechanism.
Further insights have been obtained from the analysis of SBP and R-R
sequences that are in opposition to the expected baroreflex-mediated response. Reflexes operating with a positive feedback (i.e.,
hypertensive/tachycardic and hypotensive/bradycardic) and suspected to
be physiologically active in humans (58) may interact with
and oppose the negative feedback dynamic operated by the baroreflex
(58). Pathological activation of reflex mechanisms may
also oppose baroreflex responses. Activation of these reflexes may be
mediated, for example, by the stretch of the thoracic aorta
(86), or of mechanosensitive vasodepressor afferents in
the inferoposterior wall of the left ventricle (1). During
vasovagal syncope, bradycardia and hypotension induced by ventricular
mechanoreceptors overwhelm the reflex compensatory vasoconstrictor and
tachycardic action of baroreflexes (1). Finally, central
inhibitory or excitatory influences on baroreflex responses to pressure
changes might also contribute to the state-related differential
baroreflex sensitivity reported during sleep (96, 117).
This state-related modulation of baroreflex function during sleep is
crucial in permitting simultaneous reductions in HR, blood pressure,
and MSNA during non-rapid eye movement (REM) sleep (111)
(Fig. 1). Similarly, rapid increases in
blood pressure, HR, and sympathetic activity during intrinsic changes
in brain state, as is evident during REM sleep, as well as in response to external stimuli that may induce an alerting or arousal response from sleep, relate directly to central modulation of baroreflex control. Intermittently, during REM and during arousal, the rapid transition from a condition of slow HR, low blood pressure, and low
sympathetic activity, to conditions permissive of simultaneous tachycardia, sympathetic activation, and pressure surges, speaks to the
plasticity of baroreflex dynamics (both gain and set point) and the
magnitude of the influences of changes in consciousness and central
neural processing on baroreflex control characteristics.
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Fig. 1.
Recordings of sympathetic nerve activity (SNA) and mean
blood pressure (BP) in a single subject while awake and while in stages
2, 3, 4, and rapid eye movement (REM) sleep. As non-REM sleep deepens
(stages 2 through 4), sympathetic nerve activity, heart rate, and blood
pressure gradually decrease together, suggesting a sleep-related
modulation of the baroreflex. By contrast, heart rate and blood
pressure are labile during REM sleep, together with a profound increase
in both the frequency and the amplitude of sympathetic nerve activity.
[Reproduced with permission from Somers et al. (111).]
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Given the complexity of neural circulatory control mechanisms in the
intact organism, the baroreflex is not always effective in overcoming
nonbaroreflex influences on blood pressure. As a result, in
physiological conditions, the baroreflex sequences are often
interspersed with SBP changes that are not coupled with reflex changes
in R-R modulation. Moving from this observation, a new index has been
proposed to quantify baroreflex activation in modulating HR, the
baroreflex effective index (19). With the use of this
approach, in normal subjects, it has been shown that the arterial
baroreflex induces beat-to-beat changes in pulse interval in response
to only 21% of all the ramps in blood pressure. This effectiveness is
particularly low during the night, when, by contrast, baroreflex gain
is particularly high (Fig. 2). Baroreflex effective index and baroreflex sensitivity are not redundant measures, but rather provide data on different aspects of baroreflex control of
the heart. Baroreflex effective index quantifies the number of times
the baroreflex is clearly effective in driving the sinus node, whereas
baroreflex sensitivity quantifies the power of the reflex when this
drive is effective (19).
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Fig. 2.
Hourly profile of baroreflex effectiveness index over
24 h (top) and hourly profile of baroreflex sensitivity
(bottom) in healthy control subjects. These different
aspects of baroreflex function do not have similar profiles through the
day. SBP, systolic blood pressure. [Reproduced with permission from Di
Rienzo et al. (19).]
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Recently, other methods have been proposed addressing the
"causality" in the estimate of the spontaneous baroreflex, i.e., only selecting the fraction of R-R variability driven by changes in
SBP. Among them, one method is based on the analysis of the statistical
dependence "Z" between SBP and HR, where the baroreflex is
determined only for selected values of SBP and HR that are characterized by a strong probability of dependence (14,
55). Another approach, the causal parametric method
(95), evaluates the baroreflex by fixing the temporal
direction of the influences of SBP on R-R and "disentangles the
baroreflex pathway from mechanisms driving R-R interval independently
of SBP" (95). These approaches have been validated in
animal models. However, their relevance and application to human
cardiovascular disease condition remains to be defined.
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ARTERIAL BAROREFLEX AND CARDIOVASCULAR VARIABILITY |
Linear and nonlinear dynamics of cardiovascular variability.
Cardiovascular variability comprises a very complex interaction between
hemodynamic, humoral, and electrophysiological variables, integrated by
a sophisticated system of controllers within the autonomic and central
nervous systems (33, 121, 122).
Linear and nonlinear dynamics have been demonstrated within the
variability of the cardiovascular system (for reviews, see Refs.
29, 63, 66, 85,
112, 121, 122). In addition to the periodic oscillatory behavior observed in arterial blood pressure, R-R interval, and peripheral sympathetic activity (66, 85, 112), a less specific variability occurs with nonperiodic
behavior, which can be described by methods based on nonlinear system
theory ("chaos theory and fractal analysis") (29, 63, 121,
122). Although the physiological basis for this nonharmonic
beat-to-beat behavior, which extends over a wide time scale range
(seconds to hours), is still unsettled, evidence is increasing that
this fractallike variability may encode clinically relevant information (10, 29, 40, 64).
More detailed information is available on the oscillatory
behavior observed in arterial blood pressure, R-R, and sympathetic activity, ranging, in humans, between 0 and 0.5 Hz. These oscillations are affected significantly by the autonomic nervous system (66, 85, 101, 112), acting in part through the arterial baroreflex.
During normal quiet breathing there is a strong temporal relationship
between respiration and autonomic outflow. The consensus of opinion is
that the high-frequency (HF) respiratory component of R-R interval
variability (~0.2-0.3 Hz) primarily reflects respiration-driven vagal modulation of sinus arrhythmia (112). Administration
of atropine or other parasympathetic blocking agent virtually abolishes this component of HR variability (4). Nonneural mechanical mechanisms, linked to respiratory fluctuations in cardiac transmural pressure, atrial stretch, and venous return, are also determinants of
HF power, and may become especially important after cardiac denervation
(6). The relative contribution of the arterial baroreflex
to this HF component is still not fully accepted (16, 23,
94). A further caveat is that in any assessment of relative power distribution on low-frequency (LF) and HF components, it is
crucial to ensure that the respiratory pattern is limited to the HF
component (8). LF components in respiration diminish the
values of the LF component of cardiovascular variability in helping to
understand the autonomic characteristics of cardiovascular control.
Although the primary source (or sources) of the slower nonrespiratory
oscillation (~0.1 Hz) is still controversial (for review, see Refs.
48, 66), current evidence suggests that the
baroreflex contributes substantially to LF oscillations in blood
pressure, R-R interval, and MSNA variability (2, 13, 18, 20,
108). LF oscillation in the R-R interval has been related to
cardiac sympathetic modulation resulting from the baroreflex response to the LF blood pressure oscillations (feedback theory)
(108). It has been also proposed that the LF oscillation
arises from the interaction of slow sympathetic and fast vagal
responses, where baroreflex buffering of the HF respiratory-induced
blood pressure oscillations results in resonant LF oscillations due to
the delay in the slow conducting sympathetic control loop of the
baroreflex (18). Indeed, baroreceptors, stimulated by
changes in blood pressure, induce fast responses to the heart and slow sympathetic withdrawal to the vessels. The delay in the sympathetic branch of the baroreflex in turn determines a new oscillation, which is
sensed by the baroreflex, which induces a new oscillation in the HR.
Studies on sinoaortic denervation confirm the considerable contribution
of the baroreflex in the strength of the LF oscillation of
cardiovascular variability, by showing a consistent reduction in LF
power in R-R and blood pressure variability after baroreceptor deafferentation (13, 20). However, a residual variability is still present in both R-R and blood pressure, organized in a
definite LF peak that is eliminated with ganglionic blockade. Therefore, the baroreflex may not be the only determinant of the LF rhythm.
A number of studies suggest that the LF component in the cardiovascular
system is a marker of sympathetic modulation of central origin (for
reviews, see Refs. 65, 73). In anesthetized,
vagotomized, and sinoaortic-denervated cats, both LF and HF components
have been detected in the discharge variability of medullary neurons localized in areas involved in the regulation of sympathetic nerve activity (72). In humans, an increased LF component in R-R
variability has been documented in various conditions known to decrease
baroreflex gain and increase sympathetic outflow (tilt, mental stress,
exercise). An oscillatory component in the LF range can be observed in
blood pressure and R-R variability during apnea, i.e., in absence of peripheral inputs (90). Finally, in patients with severe
heart failure, restoring hemodynamic function by the implantation of a
left ventricular device may also restore the LF component in R-R
variability of the native heart, even in the absence of any organized
blood pressure variability pattern (17). Because in this
model the native HR variability is uncoupled from blood pressure variability, the restoration of the LF oscillation independent of any
oscillation in blood pressure suggests that this LF rhythm may be a
fundamental property of central autonomic outflow (17).
An LF rhythm, which could be independent from neural inputs, has also
been described in the vasomotor tone in animals as well as in humans
(98, 118). In conditions of baroreflex unloading, such as
with sodium nitroprusside, increases in sympathetic activity and R-R
interval are accompanied by clear increases in LF power of these
measurements (118). In the same experiment, during
hypotension after 
1-selective blockade (by
phentolamine), LF power in cardiovascular variability is attenuated,
despite the reflex tachycardia and increased sympathetic nerve traffic,
suggesting that -adrenergic transmission within the baroreflex loop
appears to contribute importantly to LF oscillation. However,
phentolamine did not suppress completely the LF oscillations in
cardiovascular variability, suggesting the possibility that LF
vasomotor oscillations may persist even in the absence of intact
neurovascular transmission. These neural-independent oscillations could
either indicate the presence of "autoregulatory" properties
(98) or be an expression of the modulation operated by the
nitric oxide system (79), as described below.
Further insights from baroreflex denervation.
Baroreflex deafferentation by sinoaortic denervation
results in an increase in average arterial blood pressure and large
fluctuations in blood pressure variability (102). As
mentioned above, animal studies report that arterial baroreceptor
denervation induces selective changes in the spectrum of R-R and
blood pressure variabilities (13, 20, 45). There is a
consistent reduction in LF power in R-R variability, with or without
reduction in HF and with or without changes in the overall R-R interval
variance (markedly decreased in cats, unchanged in rats and in dogs).
Conversely, the overall blood pressure variance increases, because of
an increase in the very low frequency (VLF) components (<0.03 Hz),
whereas the faster fluctuation in LF appears to decrease. HF
respiratory-related fluctuations do not change. These findings suggest
that in several species the baroreceptor reflex exerts its major
buffering effect on fluctuations occurring in the VLF band.
Baroreflex, nitric oxide, and cardiovascular variability.
Blood pressure variability is also affected by the nitric oxide system
(45, 77, 79). Blockade of nitric oxide synthesis leads to
an increase in blood pressure variability due to an increase in the
variability at higher frequencies (45, 79). The
combination of nitric oxide blockade and infusion of nitroprusside (the
latter infused to restore the values of blood pressure and HR to
physiological levels and reduce consequent baroreflex activation)
elicited a marked increase in blood pressure variability in the
frequency range between 0.2 and 0.6 Hz (79), corresponding
to that frequency that seems mainly influenced by the sympathetic
nervous system in rats (44).
Therefore, the arterial baroreflex and the nitric oxide system are both
involved in the short-term regulation of blood pressure, modulating the
average value and variability of arterial blood pressure. However,
although the baroreflex and nitric oxide both show similar strength in
buffering blood pressure fluctuations, they show differences in the
frequency range of their actions.
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PHYSIOLOGICAL CHANGES IN BAROREFLEX FUNCTION |
A multitude of physiological factors may influence baroreflex
function. These influences will be exemplified below by a focus on effects of aging, physical deconditioning, and physical
training. The important effects of sleep were addressed earlier.
Effects of aging.
Aging is associated with significant cardiovascular modifications
(for review, see Ref. 24). Arterial baroreflex modulation of HR and sympathetic activity may be decreased in older individuals (26, 70). In rats, an impaired baroreflex control of
cardiac vagal function in response to both loading and unloading of
baroreceptors, and depressed renal sympathetic activity during
unloading of baroreceptors, have been reported (42).
Preservation of the bradycardia produced by electrical stimulation of
the vagus nerve, as well as by acetylcholine injection, supports the
hypothesis that the impaired cardiac-vagal baroreflex control in aged
rats does not reflect dysfunction in the efferent branch, but possibly
in the sensory or central components of the reflex arc
(42). Vascular compliance is an important determinant of
the magnitude of deformation and, hence, activity of the baroreceptors.
In the presence of a high compliance, the same pulse pressure can
result in increased baroreceptor firing (50). A large
cohort study in sedentary humans suggests that carotid artery
compliance may play an important mechanistic role in the age-associated
reduction in cardiovagal baroreflex sensitivity (70).
Effects of physical deconditioning.
A major cardiovascular effect of deconditioning after prolonged bed
rest or microgravity in spaceflight is the predisposition to
orthostatic intolerance (for review, see Ref. 37). Among the potential mechanisms contributing to orthostatic intolerance associated with deconditioning (including hypovolemia, inadequate maintenance of stroke volume, and vascular dysfunction) is altered autonomic function (46, 68, 105). After bed rest or
spaceflight, baseline arterial baroreflex regulation of HR is reduced
(46). In rats, after 14 days of hindlimb unloading,
sympathetic activation to muscle, renal, and lumbar vascular beds
during a hypotensive stimulus appears to be blunted (68).
In humans, after 14 days prolonged bed rest, postural hypotension in
orthostatic intolerant subjects is associated with blunted responses of
MSNA (Fig. 3) and total peripheral
resistance during 60° head up tilt (105). Taken
together, these findings suggest an impairment of reflex mechanisms,
cardiac and peripheral, to compensate for the diminished stroke volume.
Arterial baroreflex dysfunction could be due, at least in part, to
changes in central nervous processing of baroreceptor afferent input
(possibly involving altered function at the level of the rostral
ventrolateral medulla), rather than to compromise in the baroreceptors
themselves (69).
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Fig. 3.
Effect of 14 days head-down bed rest on percent increase
in total mean sympathetic nerve activity (MSNA) between supine and
30° and 60° of head-up tilt (HUT). Comparisons are between subjects
who were orthostatically tolerant (A) and intolerant
(B) after prolonged bed rest. Orthostatic intolerance was
associated with a blunting of the sympathetic response to 60° HUT.
*Significantly different from pre-bed rest condition (P < 0.05). [Reproduced with permission from Shoemaker et al.
(105).]
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One of the key adaptations to bed rest is a reduction of plasma volume,
which may itself alter baroreflex sensitivity (43). The
arterial cardiac baroreflex appears to be similarly impaired after
head-down bed rest (chronic hypovolemia plus deconditioning) and after
acute hypovolemia, suggesting that the reduced cardiac baroreflex gain
may be due primarily to a reduction of plasma volume. By contrast, a
different and opposite behavior is shown at the level of SBP
variability, which reflects the influence of vascular sympathetic drive
and which is increased during hypovolemia and unchanged after bed rest.
An interesting aspect is that an altered response of the peripheral
circulation to mental stress has also been described after head down
bed rest in healthy subjects (47). Although the
sympathetic drive (MSNA) in response to mental stress was higher, the
responses of blood flow (increased) and vascular resistance
(decreased), observed before head down bed rest, were abolished after
head down bed rest. A direct involvement of an alteration in baroreflex
function was not documented. The possible invoked mechanisms
responsible for this altered vasomotor function, including
cardiovascular remodeling, are only speculative.
Effects of physical training.
Exercise training improves endothelial function (12, 106),
the major determinant of arterial compliance, and reduces sympathetic activation (15, 33), another possible factor affecting the distensibility of the arteries. The subsequent enhanced mechanoelastic properties of the carotid artery and aorta that may occur after training (49) could theoretically favor an increase in the
baroreflex gain.
In spontaneously hypertensive rats, also characterized by a depressed
baroreflex and high sympathetic cardiovascular tone, exercise training
has been shown to attenuate the sympathetic drive to the heart and to
produce an antihypertensive effect, which results from the reduction in
HR and cardiac output rather than from decreased peripheral resistance
(106; for review, see also Ref. 54). A marked improvement
in baroreflex sensitivity is also documented in accounting for some of
these benefits (106). In normotensive rats, an improvement
was observed only in the baroreflex hypotension/tachycardia axes,
whereas, by contrast, the hypertension/bradycardia reflex was
attenuated (81). Moreover, although physical training
seemed to be effective in reducing the baseline sympathetic activity to
the kidney, baroreflex modulation of renal sympathetic activity
appeared to be attenuated (81).
In humans, the effect of exercise training on baroreflex sensitivity
and HR variability seems to be variable, depending on the category of
subjects considered.
In sedentary normal subjects, exercise training has been reported to
improve the baroreflex modulation of sympathetic nerve activity
(33, 51), whereas the effect on the cardiac axis of the
reflex is controversial (33, 51, 61).
Conversely, aerobic exercise can modulate the baroreflex
depression associated with aging (71) and
hypertension (87, 110). In patients with borderline
hypertension, an endurance training program is not only accompanied by
prolongation of R-R and lower daytime ambulatory intra-arterial blood
pressure but also by prolongation of the R-R interval during sleep with
marked increases in R-R variability (110) (Fig.
4). Remarkably, blood pressure during sleep is not lowered by endurance training. The simultaneous blood pressure reduction accompanied by a slowing of HR is accompanied by an increase in measurements of baroreflex gain using the
phenylephrine bolus technique. Thus the tachycardia, higher blood
pressures, decreased R-R variability, and lower baroreflex gain that
are thought to characterize early hypertension (8, 74) are
all opposed and reversed in part by endurance training.
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Fig. 4.
Frequency histograms of R-R intervals in a single subject
before and after training. Thick lines, fit; thin lines, unfit. With
increased fitness, mean R-R is prolonged and R-R variability increased
during waking hours (top) and especially during sleep
(bottom). These increases in R-R and R-R variability are
accompanied by increases in baroreflex gain (not shown). [Reprinted
with permission from Elsevier Science (110).]
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After myocardial infarction, a slight improvement in cardiac vagal
responsiveness seems to be a spontaneous phenomenon, independent of the
intervention of training (60). By contrast, in
post-coronary surgery patients, the significant increase in functional
capacity after a short but intense training program is associated with a considerable improvement in baroreflex gain (41).
In patients with chronic heart failure, the improvement in peripheral
hemodynamics appears to be a major factor responsible for the
beneficial effects of physical training (for review, see Ref.
113). Data in trained heart failure patients show a
correction of the endothelial dysfunction (35) and an
improvement in artery compliance (89) with a decrease of
peripheral vascular resistance and an increase in muscle blood flow
(35). There is also evidence that physical training
attenuates sympathetic overactivity and improves HR variability and its
vagal components (15). These mechanisms have been invoked,
among others, in the improved outcome after physical training
(5).
Any analysis of the effects of endurance training on baroreflex
characteristics must take into account the potential confounding effects of acute exercise (109). Immediately after
exercise, HR is faster and blood pressure is higher. Bolus
phenylephrine measurements of baroreflex gain show marked
suppression of baroreflex sensitivity. By 30-45 min after
cessation of exercise, HR approaches baseline levels and blood pressure
is normal or even lower. At this time, baroreflex gain is markedly
increased. It is therefore important that baroreflex gain in
association with endurance training is not measured shortly after an
acute bout of exercise because exercise alone may confer a short-term
improvement in baroreflex gain, even in individuals studied before
undergoing an endurance training regimen. It is important that
measurements of baroreflex gain reflect the effects of training rather
than effects of a single bout of exercise.
Baroreflex and the kidney: neural and humoral interactions.
Neural mechanisms contribute importantly to acute changes in arterial
blood pressure, whereas humoral (renin-angiotensin-aldosterone system)
and autoregulatory mechanisms (i.e., vascular stress-relaxation, capillary fluid shift, and kidney excretory function) have slower and
more sustained effects on blood pressure control (34).
However, neural and humoral mechanisms are closely linked. For
instance, increased levels of brain ANG II, such as occurs in Dahl
salt-sensitive rats during high sodium intake, affect the tonic level
of sympathetic activity as well as the magnitude of baroreflex-induced
changes in sympathetic traffic (39, 80). In humans with
mild to moderate hypertension, the marked increase in plasma renin
activity induced by a low-sodium diet has been shown to also be
associated with a blunted baroreflex modulation of sympathetic neural
drive (31).
Renal function is crucial to long-term blood pressure regulation
(34). The average level of blood pressure as well as the dynamic fluctuations of blood pressure can both influence the excretory
function of the kidney (78). Experimentally induced blood
pressure fluctuations in the renal artery at 0.1 Hz (corresponding to
the frequency of oscillations in the cardiovascular system influenced
by the baroreflex) have been shown to change renal fluid and sodium
excretion, thus potentially modulating longer-term blood pressure
(78). Among the possible mechanisms involved, an
attenuation in the activity of the renin-angiotensin system was
reported, as evidence of the importance of the LF oscillatory component
in renal perfusion in preventing marked increases in renin release.
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BAROREFLEX AND CARDIOVASCULAR DISEASE |
Hypertension.
Baroreflex gain may be reduced in hypertensive subjects
(74). Although it is not possible to establish the causal
role of the baroreflex abnormality in essential hypertension and in any associated sympathetic activation, a depressed baroreflex gain and the
resulting increased fluctuations in SBP variability may contribute to
increased end-organ damage and adverse outcome (28).
Post-myocardial infarction.
In the post-myocardial infarction phase, both depressed HR variability
and impaired baroreflex control of cardiac function have been reported
as predictors of cardiac mortality (40, 52, 56) and
life-threatening arrhythmias (57, 64). This prognostic value is independent of other important indicators, such as electrical instability (as expressed by the presence of non-sustained ventricular tachycardia) and impairment of left ventricular ejection fraction (40, 57). The integration of traditional risk stratifiers, such as nonsustained ventricular tachycardia and left ventricular ejection fraction, with autonomic markers, has been, therefore, suggested as providing better identification of patients at risk for
cardiac and arrhythmic mortality who might benefit from aggressive strategies such as an implantable cardiac defibrillator.
A mathematical model capable of producing normal and pathological
patterns after ventricular premature beats suggests that baroreflex
function (and dysfunction) has a primary role in the genesis of HR
turbulence (i.e., fluctuations of sinus-rhythm cycle length after
perturbations such as ventricular premature beats). This turbulence may
have predictive value for mortality after myocardial infarction
(103) and may be an indirect reflection of baroreflex gain
(76).
The mechanisms mediating depressed HR variability and decreased
baroreflex sensitivity after myocardial infarction are unknown (62). Altered responsiveness of sinus node pacemaker
cells to autonomic influences, changes in central neural
processing, and alterations in cardiac afferent neural inputs due to
cardiac remodeling may be implicated. Why these abnormalities worsen
prognosis is even more difficult to say. A depressed HR variability and
depressed baroreflex gain are both expressions of, among other things,
reduced parasympathetic cardiac control. Therefore, their abnormality may reflect the inability to counterbalance sympathetic activation, which, in the presence of electrical instability, such as a ventricular premature beat, can induce life-threatening arrhythmias. Recently, it
has been suggested that the fractallike variability of R-R is even more
sensitive than traditional measures of R-R variability in predicting
overall cardiac and arrhythmic death after myocardial infarction.
Although the mechanistic basis for this beat-to-beat behavior is still
unclear, the loss of the dynamic complexity of the variability signal
may be an index of loss of adaptability to the continuously changing
environmental requirements (29, 63).
Heart failure.
Depressed HR variability and deranged baroreflex sensitivity are
commonly observed in patients with heart failure (114) and have been described even in early stages of ventricular dysfunction (32). The severity of the impairment appears to be related
to the degree of functional compromise (75, 114) and the
level of sympathetic activation (27, 116). Impaired
baroreflex function is an attractive candidate mechanism to explain the
heightened sympathetic activation in heart failure. However, some
studies suggest that, although the arterial baroreflex control of HR
(2) and cardiac norepinephrine spillover (82)
are impaired, the arterial baroreflex control of peripheral sympathetic
outflow is preserved and rapidly responsive in human heart failure (3; for review, see Ref. 25). These studies suggest that
factors other than baroreflex dysfunction may be implicated in the
sympathetic over-activation in heart failure.
In these patients, despite direct evidence of high levels of
sympathetic activation (increased cardiac and total norepinephrine spillover and MSNA) (36, 59), there is a blunting or
absence of the LF component of R-R and SNA (83, 116). The
observed dissociation between sympathetic drive and LF power in the
power spectra of cardiovascular variability implies that the
traditional paradigm linking increased sympathetic drive to increased
LF power in normal subjects cannot simply be extrapolated to include
pathological conditions such as severe heart failure, where all
homeostatic mechanisms are mobilized at close to maximum levels with
little or no reserve to maintain variability. In particular, how this dissociation between LF power and sympathetic activation relates to any
baroreflex abnormalities in patients with heart failure remains unclear.
Importantly, blunted or undetectable LF components in R-R variability
are associated with worsening clinical status and poorer outcome
(75, 116). We can speculate that attenuated or absent LF
oscillation in the cardiovascular system and, thereby, in renal perfusion (78), could contribute to the marked increase in
renin-angiotensin activity observed in heart failure.
| |
CENTRAL NEURAL CONTRIBUTIONS TO BAROREFLEX DYSFUNCTION |
Many central neural structures are involved in the regulation of
the cardiovascular system and contribute to the integrity of the
baroreflex. Acute brain injuries may induce baroreflex dysfunction and
impair cardiovascular variability. The severity of neurological injury
and the outcome are related to the change in cardiovascular variability
and blunted baroreceptor sensitivity (Fig.
5) (30). Brain death is
characterized by attenuated variability and baroreceptor sensitivity.
Extensive unilateral infarction of the brain stem in the region of the
nucleus of the solitary tract may result in baroreflex dysfunction,
increased sympathetic activity, and paroxysmal neurogenic hypertension
(93). Among the supramedullary structures, the insular
cortex (the dorsal section of the rhinal sulcus) seems to be
importantly involved in cardiovascular regulation (for review, see Ref.
120). Although the precise role of this nucleus is not
clearly understood, animal studies report that 1) unilateral
lesions of the insula elicit myocardial damage and cardiac arrhythmias
(84); 2) focal cerebral ischemia leads
to transient elevations in blood pressure and HR only if the insula is
involved (91); and 3) blockade of synaptic transmission through the insula (by local injection of lidocaine) significantly decreases the slope of baroreflex gain as evaluated by
the reflex bradycardic response to phenylephrine (100).
These findings suggested the speculation that baroreflex dysfunction could be a potential mechanism involved in the cardiac effects observed
after a stroke in this region.
View larger version (30K):
[in this window]
[in a new window]
|
Fig. 5.
Heart rate and blood pressure variability, power spectral
density, and transfer function magnitude plots for 3 patients with
different degrees of neurological injury. A: normal.
B: moderate injury. C: brain death. Note changes
in y-axis scales among graphs and near-zero levels for all
variables during brain death. [Reproduced with permission from
Goldstein et al. (30).]
|
|
In cardiovascular disease conditions, particularly those that have been
associated with severe hypotension or syncopal episodes, either brief
ischemia or brief profound hypotension may conceivably contribute to abnormalities in cardiovascular control and abnormal variability on a central neural basis, rather than because of a direct
and selective dysfunction of the baroreflex. Moreover, in patients with
ischemic heart disease and/or heart failure who also have
baroreflex dysfunction and impaired cardiovascular variability, we
cannot exclude that damage in the brain, such as lacunar infarction and
other ischemic changes in cardiovascular control areas, might be implicated in the associated autonomic and hemodynamic abnormalities.
| |
SUMMARY |
The baroreflex is an important contributor to short-term blood
pressure control and to cardiovascular variability patterns. Although
rapid and dynamic physiological functions, such as breathing, importantly affect baroreflex function, other influences such as aging
and physical deconditioning must be recognized when interpreting changes in baroreflex function and cardiovascular variability. Baroreflex effects may feed back into changes in baroreflex function through nonneural mechanisms such as sodium retention and consequent changes in intravascular volume. Cardiovascular disease overall has
been linked to baroreflex dysfunction and variability abnormalities. Some of the abnormality in variability and baroreflex function may be
secondary to dysfunction at a central neural level. Last, we need to
consider the possibility that the prognostic information provided by
baroreflex dysfunction and impaired variability may, at least in part,
be the result of "nonneural" consequences of impairments in
baroreflex function and cardiovascular variability, such as sodium
retention and activation of the renin-angiotensin system.
| |
ACKNOWLEDGEMENTS |
Dr. Lanfranchi and Dr. Somers are supported by National Institutes
of Health Grants HL-65176, HL-70602, HL-61560, and M01-RR00585 and by
the Dana Foundation. Dr. Somers is an Established Investigator of the
American Heart Association.
| |
FOOTNOTES |
Address for reprint requests and other correspondence:
V. K. Somers, Mayo Clinic, 200 Second St. SW , Do-4-350, Rochester, MN 55905 (E-mail:
somers.virend{at}mayo.edu).
10.1152/ajpregu.00051.2002
| |
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TOP
ABSTRACT
INTRODUCTION
