Vol. 277, Issue 4, H1361-H1368, October 1999
Cardiac autonomic responses to volume overload in normal
subjects and in patients with dilated cardiomyopathy
L.
Spinelli1,
M.
Petretta1,
F.
Marciano2,
G.
Testa1,
M. A. E.
Rao1,
M.
Volpe3, and
D.
Bonaduce1
1 Institute of Internal
Medicine, Cardiology and Heart Surgery, University of Naples Federico
II, 80131 Naples; 2 Institute of
Cybernetics, National Research Council, 80072 Naples; and
3 Department of Experimental
Medicine and Pathology, University of Rome "La Sapienza," 00161 Rome, and Istituto di Ricovero e Cura a Carattere Scientifico, Istituto
Neurologico Mediterraneo, 86077 Pozzilli, Italy
 |
ABSTRACT |
This study
evaluated the effects of acute isotonic volume expansion on heart rate
variability (HRV) in 10 patients with dilated cardiomyopathy (DCM) and
in 10 age- and sex-matched normal volunteers. Echocardiographic left
ventricular volumes and HRV measurements by continuous Holter recording
were assessed at baseline, at 60 and 120 min during intravenous saline
load (0.9% NaCl, 0.25 ml · kg
1 · min1),
and 60 min after infusion was terminated. Data analysis was performed
by repeated-measures ANOVA. After volume expansion, left ventricular
ejection fraction increased (F = 9.8;
P < 0.001) in normal subjects and
decreased (F = 8.7;
P < 0.001) in DCM patients. During
volume expansion a significant difference was also detectable between
the two groups in root-mean-square successive difference (F = 25.2;
P < 0.001), percentage of
differences between successive normal R-R intervals >50 ms
(F = 97.6;
P < 0.001), high-frequency power
(F = 50.1;
P < 0.001), and low-frequency power
(F = 41.6; P < 0.001), all of which reflect
parasympathetic modulation of heart rate; in fact, these measurements
increased in normal subjects and decreased in DCM patients. In normal
subjects, the increase in HRV measurements during volume expansion
suggests a parasympathetic activation, mediated by stimulation of
cardiopulmonary and arterial mechanoreceptors. On the contrary, in DCM
patients the parasympathetic withdrawal, already detectable at
baseline, increases during volume expansion.
heart rate variability; isotonic volume expansion; left ventricular
dysfunction
| |
INTRODUCTION |
ACUTE ISOTONIC VOLUME EXPANSION has been utilized to
unmask abnormalities of cardiovascular and renal responses in patients with idiopathic dilated cardiomyopathy (DCM) and asymptomatic to mildly
symptomatic heart failure (28, 29). In particular, it has been reported
that in DCM patients volume expansion is followed by a reduction in
ejection fraction with a paradoxical increase in forearm vascular
resistance even in patients with basal hemodynamic, hormonal, and renal
profiles still in the normal range (28, 29). An abnormal reflex control
of the cardiovascular system with a neurohumoral excitation is
currently considered responsible for this paradoxical hemodynamic
response (11). Heart rate variability (HRV) has proven a valid
noninvasive technique for assessing cardiac autonomic control (3, 24).
Furthermore, changes in HRV have recently been found in patients with
chronic heart failure and have been reported to be associated with the progression from mild to moderate heart failure (19). The aim of the
present investigation was to evaluate cardiac autonomic control in DCM
patients with mild heart failure symptoms during isotonic water
loading. The results could help to clarify the mechanisms of
neurohumoral excitation and of parasympathetic withdrawal commonly
observed in the early stage of heart failure.
| |
METHODS |
Study patients.
The overall study population included 10 patients with idiopathic DCM
and chronic, stable, mild heart failure and 10 age- and sex-matched
normal volunteers. The investigation conforms with the recommendations
of the Declaration of Helsinki, and the study protocol was approved by
the ethical committee of our institution. All subjects gave written,
informed consent before entering the study. The patients, 7 men and 3 women ranging in age from 36 to 56 yr (mean ± SD: 49 ± 6 yr)
were recruited by selection of consecutive patients in the outpatient
clinic for cardiovascular diseases of our institution. Exclusion
criteria included any other major disease; ischemic heart disease;
hypertension; diabetes; atrial fibrillation or severe ventricular
arrhythmia; renal failure; recent acute cardiac decompensation, as
defined by the sudden accumulation of pulmonary congestion or
peripheral edema; valvular disease or significant mitral regurgitation;
and cardiothoracic anatomy not allowing satisfactory and reproducible
echocardiographic recordings. The diagnosis of DCM was based on the
exclusion of any obvious underlying cause of heart failure during
routine evaluation. In particular, no patient had a history of angina
or myocardial infarction, and all patients had undergone coronary
angiography showing normal coronary arteries. The definition of mild
heart failure was based on the following criteria: no reduction (2 patients) or mild reduction (8 patients) in functional capacity
according to the New York Heart Association classification (class I or
II); mild to moderate limitation of exercise capacity, as determined by
cardiopulmonary exercise testing using a standard protocol (upright
bicycling with a stepwise increase of 10 W/min) (mean exercise duration
in patients was 9.7 ± 0.5 min; peak oxygen consumption averaged 18 ± 0.8 ml · kg1 · min1);
echocardiographic end-diastolic left ventricular diameter 
56 mm; and
left ventricular ejection fraction, as determined by equilibrium radionuclide angiography, <45% on at least one measurement within 3 mo before the study. At the time of their first visit to the outpatient
clinic, seven patients were undergoing treatment with angiotensin-converting enzyme (ACE) inhibitors, whereas digitalis and
diuretics were being given to four and five patients, respectively.
Experimental protocol.
All drug therapy was discontinued at least 1 wk, and ACE inhibitor at
least 2 wk, before the study. Alcohol, caffeine, cigarettes, and
physical exercise were all prohibited within 24 h of the study. After
being admitted to the clinic ward, all subjects were maintained on a
daily diet containing 100 meq of sodium, 50 meq of potassium, and 1,500 ml of water. Daily 24-h urine collections were analyzed for sodium,
potassium, and creatinine excretion. When a satisfactory equilibrium
between sodium and water excretion was achieved, the patients underwent
the study protocol on two consecutive days, as previously described
(28). On the first day, patients underwent 24-h Holter recording. The
recording started between 8:00 and 10:00 AM, and patients were asked to
record the time they went to sleep and the time they awakened. All
patients reported sleeping normally during the night they were
monitored. When this 24-h monitoring was terminated, a second Holter
recording was started; after voiding, the patient assumed a comfortable
lying position and an intravenous line was inserted into a superficial
forearm vein. The temperature (22°C) and the lights of the study
room were maintained constant. After 60 min, an intravenous isotonic saline load (0.9% NaCl, 0.25 ml · kg1 · min1)
was started and maintained at a constant rate for 2 h. Arterial blood
pressure was measured at 10-min intervals by a standard sphygmomanometric technique. Heart rate was continuously monitored by
electrocardiogram (ECG) lead II. M- and B-mode echocardiograms were
recorded for measurements of cardiac dimensions, calculation of left
ventricular ejection fraction, and estimation of stroke volume and the
derived parameters before the isotonic saline load was started, at
60-min intervals during the saline load, and 60 min after its
termination. At the same time, urine output was measured. Thereafter,
the Holter recording was interrupted and the study session terminated.
The same study protocol was performed in control subjects.
Echocardiographic measurements.
Wide-angle, two-dimensional echoes were recorded with a phased-array
sector scanner (77020 AC, Hewlett-Packard, Andover, MA). All studies
were videotaped on 3/4-in. tape with the use of videocassette recorders equipped with a backspacer search module, which allows frame-by-frame bidirectional playback. The video frame rate of the
system was ~60 frames/s. All patients were studied while in a
comfortable lying position with multiple views through the apical window. Two views were selected for measurements: an apical
four-chamber view and an apical two-chamber view. The left ventricular
long axis
(Lmax) was
measured at end diastole as the longest major axis in either of the two
apical views. The measurements of
Lmax were rounded
off to the closest whole number to ensure reproducibility. Left
ventricular end-diastolic area was measured by using the largest of all
the left ventricular minor axes measured. Left ventricular
end-diastolic volume (in ml) was calculated according to the
single-plane ellipse method as EDV = 
(EDA2)/(
· Lmax),
where EDA is end-diastolic area (13). The same measurements were
undertaken in end systole to calculate end-systolic volume. Ejection
fraction was measured using the averages of all the end-diastolic and
end-systolic volumes (13). All studies were performed by the same
investigator and read independently by two experts unaware of the
protocol. The readings that were obtained showed correlation for both
Lmax
(r = 0.96;
P < 0.001) and end-diastolic area
(r = 0.95, P < 0.001). Excellent correlations between the two observers were also obtained for the measurements of
end-diastolic (r = 0.96, P < 0.001) and end-systolic volume (r = 0.95, P < 0.001). The variability of
multiple measurements of volumes over a period of 2 h did not exceed
3.5%. Stroke volume was derived as the difference between
end-diastolic volume and end-systolic volume, and cardiac output and
total peripheral resistance were estimated by using standard formulas.
In our laboratory, the echocardiographic measurements of stroke volume
were significantly correlated with the measurements obtained using the
thermodilution technique (r = 0.88, P < 0.01).
Processing 24-h Holter recordings.
All 24-h Holter recordings were analyzed at the National Research
Council cybernetics laboratory, as previously described (5). The
two electrocardiographic analogic channels were read via a modified
Teac-Tascam 234 Syncaset tape deck (Teac, Tokyo, Japan) and digitized
at 330 samples/s. In addition to evaluation of the usual
electrocardiographic parameters, including the identification of QRS
widths and shapes and R-R interval abnormalities, all R-R interval
sequences were stored, and each was labeled with a code number
identifying its normality or its class of abnormality. Premature
complexes and their adjacent R-R intervals, used only for timekeeping
purposes, were rejected by the software, as were electrical noise and
other aberrant electrocardiographic signals. To be eligible for the
present study, data losses per tape due to persistent rhythm anomalies
and artifacts could not exceed 10% of the entire recording or of
daytime (7:30 AM to 9:30 PM) or nighttime recordings (12:00 AM to 5:00
AM). The sequence of normal R-R (NN) intervals was analyzed to compute
time- and frequency-domain measurements of HRV (3, 24).
Time-domain measurements of HRV.
From the time series of NN intervals we calculated the time-domain
variables defined in Table 1. The standard
deviation of the NN intervals (SDNN) calculated over a 24-h period
encompasses short-term as well as long-term NN-interval variations. The
standard deviation of the average NN intervals for all 5-min segments
of the entire 24-h ECG recording (SDANN index) also evaluates long-term R-R variations, whereas the mean of the standard deviations of NN
intervals for all 5-min segments of the entire 24-h ECG recording (SDNN
index) depends on short-term R-R variations. On the other hand,
differences between successive NN intervals provide an index of cardiac
vagal control that is firmly related to short-term variations in heart
rate. Accordingly, we calculated the root-mean-square successive
difference (r-MSSD) of all NN intervals and the percentage of
differences between adjacent NN intervals exceeding 50 ms (pNN50) for
the entire 24-h recording.
Frequency-domain measurements of HRV.
The 24-h heart rate power spectrum was computed by means of the fast
Fourier transform algorithm, as previously described (5). A smooth
shape for fast Fourier transform estimates, reducing side-lobe leakage,
was obtained by cosine tapering the original time series at each end
over one-tenth of the window (2). An R-R interval function of time was
obtained from the sequence of R-R intervals as follows: from the
sequence of NN values, the sequence
NNi = NNi+1 
NNi = f(NNi,
NNi+1) was
evaluated, and from this the temporal sequence NN = f(i), where
i = 100, 200, 300 ms ... was
computed by linear interpolation with a time step of 100 ms; this is a
low-pass filtering operation that attenuates any variability above the
chosen value of the sampling frequency. The final average spectrum
provided total power and average power per band in square milliseconds.
The frequency bands explored are reported in Table 1; the ratio of low-
to high-frequency power was calculated from the absolute values of
these two components. An epoch of 300 s and a sampling period of 293 ms
(1,024 samples/epoch) were chosen to cover the entire range with a
sufficient number of frequency samples in each band as follows: very
low frequency, 12 samples; low frequency, 34 samples; high frequency,
75 samples.
To evaluate the effect of saline loading on cardiac autonomic control
in DCM patients and in normal subjects, four sets of HRV measurements
were obtained by averaging three consecutive 5-min segments. For this
purpose, time-domain measurements of long-term HRV (SDNN and SDANN
indexes) were not calculated. The first set of measurements was
obtained at steady state, just before the infusion started; the other
three sets were centered at 60 and 120 min during the infusion and at
60 min after the end of the infusion. At these same times, although
respiratory activity was not recorded, an ECG-derived respiratory
signal was obtained using an adaptation of the technique previously
described and validated by Moody et al. (18). Briefly, R wave height
measurements were obtained for each normal beat, and a time series was
constructed by plotting the R wave height versus time and analyzed by
means of the fast Fourier transform algorithm to obtain a rough
estimation of respiratory rate (21).
Statistical analysis.
Statistical analysis was performed using the SPSS statistical package.
Categorical variables were expressed as percentages; continuous data
were expressed as means ± SD. Because the distribution of the
frequency-domain measurements of HRV were skewed, the log transformation (ln) of each measure, which produces nearly normal distributions, was applied before statistical analysis was performed. Baseline data of normal subjects and DCM patients were compared by
unpaired t-test or chi-square test as
appropriate. A P value <0.05 was
considered significant. Repeated-measures ANOVA followed by post hoc
multiple comparisons with the Bonferroni correction was performed to
detect changes over time during saline load within the same group.
Between-group comparisons of the responses to saline load were tested
by two-factor ANOVA for repeated measures considering the main effects
of the independent variables "group" (normal subjects vs. DCM
patients) and "time" as well as the "time-group" interaction.
| |
RESULTS |
HRV analysis of 24-h Holter recording.
The results of HRV analysis by 24-h Holter recordings are reported in
Table 2. Average NN values were lower in
patients with DCM than in controls. Moreover, DCM patients had lower
values of time-domain measurements of HRV. Frequency-domain
measurements were also lower in DCM patients than in controls, whereas
the ratio of low- to high-frequency power was comparable between the two groups.
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Table 2.
Heart rate variability measurements over 24 h in control subjects and
in patients with idiopathic dilated cardiomyopathy
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Circulatory response to volume expansion.
Figure 1 shows the responses of systemic
and cardiac hemodynamics to saline load in the two groups. Systolic and
diastolic arterial pressure did not change during saline load, and no
difference between the two groups was detectable. In normal subjects
left ventricular end-diastolic volume
(F = 21.8;
P < 0.001), left ventricular ejection fraction (F = 9.8;
P < 0.001), stroke volume
(F = 17.4; P < 0.001), and cardiac output
(F = 9.38;
P < 0.001) increased during saline
load, whereas left ventricular end-systolic volume did not change. In
contrast, in heart failure patients both left ventricular end-diastolic
(F = 9.8;
P < 0.001) and end-systolic volume
(F = 13.6;
P < 0.001) increased, whereas left
ventricular ejection fraction, stroke volume, and cardiac output
remained unchanged. Two-factor repeated-measures ANOVA showed a
significant (P < 0.001)
between-group difference for all the echocardiographically derived
parameters; moreover, the time-group interaction was significant for
end-systolic volume (F = 14.3;
P < 0.001), left ventricular ejection fraction (F = 8.7;
P < 0.001), and stroke volume
(F = 4.7;
P < 0.005). In normal subjects
during saline load, urinary volume increased
(F = 35.1;
P < 0.001) from 2.15 ± 0.14 to
2.94 ± 0.55 ml/min at 60 min to 4.14 ± 0.69 ml/min at
120 min and 3.72 ± 0.52 ml/min at 180 min. In heart failure
patients the response of urinary volume (1.81 ± 0.10 ml/min at
baseline, 1.95 ± 0.33 ml/min at 60 min, 2.05 ± 0.28 ml/min at
120 min, and 1.81 ± 0.19 ml/min at 180 min) did not achieve
statistical significance.
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Fig. 1.
Effects of saline load on left ventricular (LV) end-diastolic (LVEDV)
and end-systolic volume (LVESV), LV ejection fraction (LVEF), stroke
volume (SV), cardiac output (CO), and systolic and diastolic blood
pressure (BP; top plots are systolic
BP and bottom plots are diastolic BP)
in patients with idiopathic dilated cardiomyopathy ( ) and in normal
subjects ( ) at baseline (B) and 60, 120, and 180 min after loading.
* P < 0.01 compared with
baseline.  P < 0.01 compared with normal subjects.
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HRV measurements and volume expansion.
Figure 2 shows the responses of heart rate
and time-domain measurements of HRV during volume expansion in the two
groups. The response to saline load in normal subjects was different
from that in DCM patients. In normal subjects average NN remained
unchanged during saline load, whereas r-MSSD
(F = 9.4;
P < 0.001), pNN50 (F = 4.1;
P < 0.05), and SDNN index
(F = 7.3;
P < 0.001) increased significantly. In contrast, in DCM patients average NN decreased during
saline load (F = 5.1;
P < 0.01), whereas r-MSSD, pNN50, and SDNN index remained unchanged. Two-factor repeated-measures ANOVA
showed a significant between-group difference in average NN
(F = 6.1;
P < 0.05), r-MSSD
(F = 25.2;
P < 0.001), pNN50
(F = 97.6;
P < 0.001), and SDNN index
(F =28.7;
P < 0.001). Also, the time-group
interaction showed a significant difference for average NN
(F = 3.2;
P < 0.05), r-MSSD
(F = 5.4;
P < 0.005), pNN50 (F = 3.3;
P < 0.05), and SDNN index
(F = 3.9;
P < 0.05). The effect of
saline load on frequency-domain measurements is shown in Fig. 3. In normal subjects saline load induced
an increase in very low-frequency (F = 32.4; P < 0.001), low-frequency
(F = 12.7; P < 0.001), and high-frequency power
(F = 30.1;
P < 0.001). In DCM patients
frequency-domain measurements did not change. The ratio of low- to
high-frequency power remained unchanged during saline load in the two
groups. When the changes in frequency-domain measurements were analyzed
by two-factor ANOVA with group as the main effect, a significant
difference was detectable between the two groups in very low-frequency
(F = 6.1;
P < 0.05), low-frequency (F = 41.6;
P < 0.001), and high-frequency power
(F = 50.1;
P < 0.001), and the time-group
interaction was significant for very low-frequency
(F = 3.8;
P < 0.01), low-frequency
(F = 5.7;
P < 0.005), and high-frequency power
(F = 6.6;
P < 0.001), confirming the different
responses of HRV to saline load between the two groups. Mean
respiratory rate, measured from the ECG-derived respiratory signal, was
higher at baseline in DCM patients than in normal subjects (0.31 ± 0.03 vs. 0.25 ± 0.04 Hz; P < 0.001) and remained unchanged in normal subjects, whereas it increased
in DCM patients (F = 12.7;
P < 0.001) and was 0.32 ± 0.03 Hz at 60 min, 0.33 ± 0.04 Hz at 120 min, and 0.32 ± 0.03 Hz at
180 min. Thus, when the two groups were compared by two-factor ANOVA, a
significant between-group difference
(F = 99.2;
P < 0.001) as well as a significant time-group interaction (F = 3.9;
P < 0.05) was detectable.
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Fig. 2.
Effects of saline load on time-domain measurements of heart rate
variability in patients with idiopathic dilated cardiomyopathy ()
and in normal subjects (). NN, normal R-R intervals; pNN50,
percentage of differences between successive normal R-R intervals that
are >50 ms; r-MSSD, root-mean-square successive difference; SDNNi,
mean of standard deviations of all normal R-R intervals for 5-min
segments. * P < 0.01 compared
with baseline. P < 0.01 compared with normal subjects.
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Fig. 3.
Effects of saline load on frequency-domain measurements of heart rate
variability in patients with idiopathic dilated cardiomyopathy ()
and in normal subjects (). VLF, very low-frequency power; LF,
low-frequency power; HF, high-frequency power; LF/HF, ratio of low- to
high-frequency power. * P < 0.01 compared with baseline.
P < 0.01 compared with
normal subjects.
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| |
DISCUSSION |
The present study demonstrates that changes in HRV measurements after
acute volume expansion differ in patients with DCM from those observed
in normal subjects. In fact, cardiac vagal control decreased in
patients with DCM during saline load but increased in normal subjects.
Moreover, the response of urinary volume to saline load was
significantly depressed in DCM patients compared with normal subjects.
These findings extend previous observations (28, 29) that demonstrate
the presence of abnormal hemodynamic, hormonal, and renal adaptation to
volume loading in mild heart failure patients.
HRV and chronic heart failure.
In our study, time- and frequency-domain measurements obtained from
24-h Holter recordings were lower in DCM patients than in normal
subjects. A clear reduction in total power of the heart rate power
spectrum and in each of its components has recently been demonstrated
in patients with chronic heart failure (10). High-frequency power
reflects the modulation of cardiac autonomic control by respiratory
frequency and depth and is considered a pure measurement of cardiac
vagal control (3, 24). Therefore, the decrease in high-frequency power
that we observed in DCM patients reflects the parasympathetic
withdrawal that is an integral component of the autonomic dysfunction
detectable in patients with asymptomatic to mildly symptomatic heart
failure (4). The decrease in low-frequency power is also commonly
observed in patients with chronic heart failure, and different
hypotheses have been proposed to connect the decrease in this frequency
band with the known sympathovagal characteristics of patients with
heart failure. Saturation of the sinus node with sympathetic traffic
has been shown to prohibit the superimposition of any variability on a
heart rate pattern (16). Accordingly, the progressive sympathetic
activation that occurs in chronic heart failure may be accompanied by a
reduction in the power of the low-frequency band. The progressive
downregulation of myocardial 
-adrenergic receptors and the reduction
of myocardial catecholamine stores may also produce a reduction in
end-organ responsiveness to sympathetic stimulation (9). Recently, van de Borne et al. (27) performed the spectral analysis of simultaneous recordings of resting muscle sympathetic nerve activity and R-R interval in patients with chronic heart failure and in age-matched control subjects. Despite the increase in muscle sympathetic nerve activity, the low-frequency components of R-R interval and nerve activity were lower in heart failure patients than in control subjects.
These authors hypothesized that the reduction in low-frequency components in heart failure patients reflects a disturbance of rhythmic
oscillations of autonomic outflow due to a central autonomic impairment
(27). Finally, it is well established that the parasympathetic arm of
the autonomic nervous system contributes to low-frequency power (8,
24). Therefore, a reduction in the parasympathetic modulation of heart
rate could compound the reduction of low-frequency power, which is
detectable with the progression of left ventricular dysfunction.
Interestingly, it has been demonstrated that in heart failure patients
the degree of autonomic dysfunction as represented by impaired HRV is
an independent predictor of mortality that is able to add prognostic
information to that of left ventricular ejection fraction (20).
Volume overload and cardiac adaptations.
Hemodynamic, hormonal, and renal adaptations to volume loading have
been widely evaluated to define the time of onset of the hormonal and
cardiorenal abnormalities in patients with mild to moderate heart
failure. Volpe et al. (28, 29) found that in DCM patients with chronic,
stable, mild heart failure, ejection fraction and stroke volume
decrease progressively during volume expansion, whereas forearm
vascular and calculated total peripheral resistances paradoxically
increase. In contrast, in normal subjects ejection fraction increases
and peripheral resistances decrease.
Therefore, the overall mechanisms of adaptation to increased preload in
patients with DCM are quite different from those operating in
physiological states. In our study, volume overload in normal subjects
was followed, as expected, by an increase in left ventricular ejection
fraction, due to an increase in left ventricular end-diastolic volume,
without changes in left ventricular end-systolic volume (Fig. 1). In
heart failure patients, volume overload induced an increase in both
left ventricular end-diastolic and end-systolic volumes with a slight
reduction of ejection fraction. These findings confirm the early
exhaustion of the preload reserve mechanism even in the early stage of
heart failure.
Volume overload and HRV measurements.
The major finding of the present study is the difference in cardiac
autonomic control during volume expansion, as revealed by HRV analysis,
between normal subjects and DCM patients. In fact, in normal subjects
we observed that saline loading was followed by a progressive increase
of high-frequency power, r-MSSD, and pNN50, measurements considered to
reflect the parasympathetic modulation of heart rate. The increase in
low-frequency power may also be ascribed to an increase in vagal
activity, because this frequency band reflects the mixed modulation by
the parasympathetic and sympathetic branches of the autonomic nervous
system (8). It is well known that, in normal subjects, a tonic
inhibitory influence on sympathetic efferent outflow from the medullary
cardiovascular centers is exerted by the activation of arterial and
cardiopulmonary mechanoreceptors (14). The left ventricle is the site
of many of these cardiac sensory receptors (6), and the principal
determinants of their activity are cardiac filling pressure, the
inotropic state of the ventricle, and the mechanical deformation of the walls in which they are located (12, 26). During volume expansion, low-pressure mechanoreceptors increase their inhibitor influence on
sympathetic efferent outflow and increase their excitatory influence on
parasympathetic outflow. This restraint effect on sympathetic efferent
outflow is responsible for the reduction of forearm vascular resistance
observed in normal subjects when the venous return to the heart is
increased, such as after leg rise (1, 17) or saline load (29). However,
it has been demonstrated that arterial baroreceptors located in the
carotid artery (15) and thoracic aorta (25) are exquisitely sensitive to deformation and may respond to minor volume changes. Therefore, it
is conceivable that the changes we observed in HRV measurements during
volume loading are, importantly, mediated also by arterial baroreceptors. The increased mechanoreceptor activity is involved in
the reflex increase in urine flow and sodium excretion as well as in
the decrease in vasopressin release, renin release, and renal
sympathetic nerve activity (23, 30).
In DCM patients, but not in controls, we observed a clear reduction in
r-MSSD, pNN50, and high-frequency power, measurements that indicate
vagal modulation of heart rate. These findings confirm that patients
with chronic left ventricular dysfunction have a significant impairment
of cardiopulmonary and arterial baroreflex mechanisms and reduced
sensitivity of mechanoreceptors with vagal afferent endings. The
reduced sensitivity of these receptors with inhibitory influence would
produce a net increase in sympathetic activity. Moreover, receptors
whose afferent fibers run along cardiac sympathetic nerves have been
also described (22). It is conceivable that during volume expansion
there is an uncontrolled stimulation of these cardiac receptors with
sympathetic afferents, leading to a further decrease in vagal
modulation of heart rate (22). Also, breathing frequency influences
vagal cardiac nerve traffic, and faster breathing rates reduce
noninvasive indexes of cardiac vagal control (7). In our study DCM
patients breathed more rapidly than normals at baseline and increased
their breathing frequency during volume load. These
differences in breathing may have contributed to the differences in
responses in HRV measurements reflecting vagal control observed in the
two groups.
Thus the response of the autonomic nervous system differs between
normal subjects and heart failure patients. In normal subjects, volume
expansion is followed by a parasympathetic activation that contributes,
along with cardiac and hormonal adaptation, to eliminate promptly the
saline load and to regulate vascular volumes. On the contrary, in
patients with left ventricular dysfunction, the progressive decrease in
HRV measurements demonstrated that the autonomic dysfunction detectable
in resting condition is more evident during volume expansion. These
abnormalities of reflex control are responsible for peripheral
vasoconstriction and consequent reduced blood flow to peripheral
tissue, and they contribute to water and salt retention in chronic
heart failure.
| |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: D. Bonaduce,
Via A. Falcone 394, 80127 Naples, Italy (E-mail: bonaduce{at}unina.it).
Received 29 January 1999; accepted in final form 19 May 1999.
| |
REFERENCES |
1.
Abboud, F. M.,
D. D. Heistad,
A. L. Mark,
and
P. G. Schmid.
Reflex control of the peripheral circulation.
Prog. Cardiovasc. Dis.
18:
371-403,
1976[Medline].
2.
Bendat, J. S.,
and
A. G. Piersol.
Random Data: Analysis and Measurement Procedures (2nd ed.). New York: Wiley, 1986, p. 391-404.
3.
Berntson, G. G.,
J. T. Bigger,
D. L. Eckberg,
P. Grossman,
P. G. Kaufmann,
M. Malik,
H. N. Nagaraja,
S. W. Porges,
J. P. Saul,
P. H. Stone,
and
M. W. van der Molen.
Heart rate variability: origins, methods and interpretive caveats.
Psychophysiology
34:
623-648,
1997[Medline].
4.
Binkley, P. F.,
E. Nunziata,
G. J. Haas,
S. D. Nelson,
and
R. J. Cody.
Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure. Demonstration in human subjects and verification in a paced canine model of ventricular failure.
J. Am. Coll. Cardiol.
18:
464-472,
1991[Abstract].
5.
Bonaduce, D.,
F. Marciano,
M. Petretta,
M. L. Migaux,
G. Morgano,
V. Bianchi,
L. Salemme,
M. Valva,
and
M. Condorelli.
Effects of converting enzyme inhibition on heart period variability in patients with acute myocardial infarction.
Circulation
90:
108-113,
1994[Abstract/Free Full Text].
6.
Coleridge, H. M.,
J. C. C. Coleridge,
A. Dangel,
C. Kidd,
J. C. Luck,
and
P. Sleight.
Impulses in slowly conducting vagal fibers from afferent endings in the veins, atria, and arteries of dogs and cats.
Circ. Res.
33:
87-97,
1973[Abstract/Free Full Text].
7.
Eckberg, D. L.
Human sinus arrhythmia as an index of vagal cardiac outflow.
J. Appl. Physiol.
54:
961-966,
1983[Abstract/Free Full Text].
8.
Eckberg, D. L.
Sympathovagal balance.
Circulation
96:
3224-3233,
1997[Free Full Text].
9.
Eisenhofer, G.,
P. Friberg,
B. Rundqvist,
A. A. Quyyumi,
G. Lambert,
D. M. Kaye,
I. L. Kopin,
D. S. Goldstein,
and
M. D. Esler.
Cardiac sympathetic nerve function in congestive heart failure.
Circulation
93:
1667-1676,
1996[Abstract/Free Full Text].
10.
Fauchier, L.,
D. Babuty,
P. Cosnay,
M. L. Autret,
and
J. P. Fauchier.
Heart rate variability in idiopathic dilated cardiomyopathy: characteristics and prognostic value.
J. Am. Coll. Cardiol.
30:
1009-1014,
1997[Abstract].
11.
Ferguson, D. W.,
F. M. Abboud,
and
A. L. Mark.
Selective impairment of baroreflex mediated vasoconstrictor responses in patients with ventricular dysfunction.
Circulation
69:
451-460,
1984[Abstract/Free Full Text].
12.
Ferguson, D. W.,
M. D. Thames,
and
A. L. Mark.
Effects of propranolol on reflex vascular responses to orthostatic stress in humans. Role of ventricular baroreceptors.
Circulation
67:
802-807,
1983[Abstract/Free Full Text].
13.
Folland, E. D.,
A. F. Parisi,
B. S. Moghihan,
D. R. Joney,
C. L. Feldman,
and
D. E. Tow.
Assessment of left ventricular ejection fraction and volumes by real-time, two-dimensional echocardiography.
Circulation
60:
760-771,
1979[Abstract/Free Full Text].
14.
Hainsworth, R.
Reflexes from the heart.
Physiol. Rev.
71:
617-658,
1991[Free Full Text].
15.
Lacolley, P. J.,
B. M. Pannier,
M. A. Slama,
J. L. Cuche,
A. P. G. Hoeks,
S. Lauren,
G. M. London,
and
M. E. Safar.
Carotid arterial haemodynamics after mild degrees of lower-body negative pressure in man.
Clin. Sci. (Colch.)
83:
535-540,
1992[Medline].
16.
Malik, M.,
and
A. J. Camm.
Components of heart rate variability. What they really mean and what we really measure.
Am. J. Cardiol.
72:
821-822,
1993[Medline].
17.
Mancia, G.,
G. Grassi,
and
C. Giannattasio.
Cardiopulmonary receptor reflex in hypertension.
Am. J. Hypertens.
1:
249-255,
1988[Medline].
18.
Moody, G. B.,
R. G. Mark,
M. A. Bump,
J. S. Weinstein,
A. D. Berman,
J. E. Mietus,
and
A. L. Goldberger.
Clinical validation of the ECG-derived respiration (EDR) technique.
Comp. Cardiol.
14:
507-510,
1987.
19.
Panina, G.,
U. N. Khot,
E. Nunziata,
R. J. Cody,
and
P. F. Binkley.
Role of spectral measures of heart rate variability as markers of disease progression in patients with chronic congestive heart failure not treated with angiotensin-converting enzyme inhibitors.
Am. Heart J.
131:
153-157,
1996[Medline].
20.
Ponikowski, P.,
S. D. Anker,
T. P. Chua,
R. Szelemej,
M. Piepoli,
S. Adamopoulos,
K. Webb-Peploe,
K, D. Arrington,
W. Bansasiak,
K. Wrabec,
and
A. J. S. Coats.
Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.
Am. J. Cardiol.
79:
1645-1650,
1997[Medline].
21.
Saul, J. P.,
Y. Arai,
R. D. Berger,
L. S. Lilly,
W. S. Colucci,
and
R. J. Cohen.
Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis.
Am. J. Cardiol.
61:
1992-1999,
1988.
22.
Schwartz, P. J.,
M. Pagani,
A. Lombardi,
A. Malliani,
and
A. M. Brown.
A cardiocardiac sympathovagal reflex in the cat.
Circ. Res.
32:
215-220,
1973[Abstract/Free Full Text].
23.
Sivananthan, N.,
C. T. Kappagoda,
and
R. J. Linden.
The nature of atrial receptors responsible of the increased urine flow caused by distension of the left atrium in the dog.
Q. J. Exp. Physiol.
66:
51-59,
1981[Abstract/Free Full Text].
24.
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.
Heart rate variability. Standards of measurement, physiological interpretation, and clinical use.
Circulation
93:
1043-1065,
1996[Free Full Text].
25.
Taylor, G. A.,
J. R. Halliwill,
T. E. Brown,
J. Hayano,
and
D. L. Eckberg.
"Non-hypotensive" hypovolaemia reduces ascending aortic dimensions in humans.
J. Physiol. (Lond.)
483:
289-298,
1995[Medline].
26.
Thorén, P. N.
Characteristics of left ventricular receptors with nonmedullated vagal afferents in cats.
Circ. Res.
40:
415-421,
1977[Abstract/Free Full Text].
27.
Van de Borne, P.,
N. Montano,
M. Pagani,
R. Oren,
and
V. K. Somers.
Absence of low-frequency variability of sympathetic nerve activity in severe heart failure.
Circulation
95:
1449-1454,
1997[Abstract/Free Full Text].
28.
Volpe, M.,
C. Tritto,
N. De Luca,
A. F. Mele,
G. Lembo,
S. Rubattu,
M. Romano,
P. De Campora,
I. Enea,
B. Ricciardelli,
B. Trimarco,
and
M. Condorelli.
Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.
J. Clin. Invest.
88:
1481-1489,
1991.
29.
Volpe, M.,
C. Tritto,
N. De Luca,
S. Rubattu,
A. F. Mele,
G. Lembo,
I. Enea,
P. De Campora,
D. Rendina,
M. Romano,
B. Trimarco,
and
M. Condorelli.
Angiotensin converting enzyme inhibition restores cardiac and hormonal responses to volume overload in patients with dilated cardiomyopathy and mild heart failure.
Circulation
86:
1800-1809,
1992[Abstract/Free Full Text].
30.
Zehr, J. E.,
J. A. Hasbargen,
and
K. D. Kurz.
Reflex suppression of renin secretion during distension of cardiopulmonary receptors in dogs.
Circ. Res.
38:
232-239,
1976[Abstract/Free Full Text].
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