(Hypertension. 1999;33:1141-1145.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Diastolic Dysfunction and Baroreflex Sensitivity in Hypertension
From the Institute of Cardiology, University of Bari (M.V.P., C.F., C.B., G.S., G.A., P.R.), and Division of Cardiology, "S. Maugeri" Foundation, IRCCS, Cassano Murge (Ba) (A.P., F. Massari, F. Mastropasqua), Italy.
Correspondence to Maria Vittoria Pitzalis, MD, PhD, FESC, Institute of Cardiology, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy. E-mail pitzalis{at}tin.it
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Abstract |
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Abstract—The determinants of diastolic dysfunction in patients with systemic hypertension are not completely known. To evaluate the possible role of age, arterial blood pressure, and baroreflex heart rate response impairment in causing diastolic dysfunction, we studied 61 patients (42 male; mean±SD age, 43.9±12 years) with newly recognized and therefore previously untreated systemic hypertension. Diastolic dysfunction was evaluated by means of Doppler echocardiography (and diagnosed as such when the early to atrial peak velocity ratio corrected to heart rate was <1), arterial blood pressure by 24-hour ambulatory monitoring, and baroreflex heart rate response by means of the spectral technique (
index) during paced (0.27 Hz) and spontaneous breathing (in a
supine position and during tilt). Nineteen patients had
diastolic dysfunction, the most powerful predictor of which
was age (r=-0.63, P<0.001). The
patients with diastolic dysfunction had significantly lower
values for spectral baroreflex gain in the high-frequency band than
those without (5.2±3 versus 8.4±5 ms/mm Hg during paced breathing,
P<0.05; 7.4±4 versus 13.3±7 ms/mm Hg in a
supine position, P<0.05; 4.3±4 versus 5±2
ms/mm Hg during tilt, P<NS). Ambulatory blood
pressure values were not significantly different in the patients with
(137±14 and 89±9 mm Hg) and without (144±11 and 82±24
mm Hg) diastolic dysfunction. In conclusion, age and
impaired baroreflex heart rate response (but not pressure overload) are
determinants of left ventricular diastolic
dysfunction in patients with newly recognized and untreated
systemic hypertension.
Key Words: hypertension, systemic • ventricular function, left • baroreflex • blood pressure monitoring, ambulatory
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Introduction |
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The cause and time of occurrence of cardiac impairment in patients with essential hypertension are not precisely known. It has been shown that diastolic dysfunction is the earliest cardiac abnormality in this patient population1 and may precede ventricular hypertrophy.2 Age and pressure load are considered possible determinants,3 whereas the role of the autonomic nervous system is still debated. Animal studies have suggested that a high sympathetic tone may favor the development of hypertrophy,4 but the role of the autonomic nervous system in the genesis of cardiac abnormalities is unclear. Some studies have reported increased sympathetic activity in hypertensive patients with cardiac hypertrophy,5 but this has not been confirmed by other authors.6 Furthermore, no data are yet available concerning the role of depressed baroreflex sensitivity in determining cardiac impairment in these patients. It is possible that it is too late for any autonomic nervous system abnormalities to be detected once hypertrophy becomes evident, and therefore the early phase of essential hypertension could offer important information on the role of autonomic nervous system activity in determining the presence of cardiac involvement.
The purpose of this study was to evaluate the role of pressure load and baroreflex heart rate response in determining the appearance of diastolic ventricular dysfunction in patients with previously unrecognized and untreated mild to moderate essential hypertension.
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Methods |
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Study Population
The study involved 61 consecutive patients referred to our outpatient clinic for previously untreated mild to moderate hypertension. Only the patients whose diastolic blood pressure was >90 mm Hg at 3 different examinations were included in the study. All of the patients were asymptomatic and underwent a full medical examination, 12-lead ECG, routine laboratory tests, and a treadmill stress test to rule out neurological disease, secondary hypertension, and coronary artery disease. Obese (body mass index >30 kg/m2) and diabetic patients were also excluded. The control group consisted of 15 nonhospitalized healthy volunteers (10 male; mean±SD age, 42±9 years).
Echocardiographic Examination
M-mode 2-dimensional echocardiography and
cardiac Doppler recordings were obtained by means of a
phased-array echo-Doppler system (HP-Sonos 500) equipped with a
2.5-Hz transducer. We examined the patients in the left lateral
recumbent position, using standard parasternal, short axis, and apical
views. The recordings were analyzed offline by 2
independent observers. M-mode recordings were obtained, and
left ventricular diastolic diameter and septal
and posterior wall thickness were measured. Left
ventricular mass index (LVMI) was obtained by dividing the
left ventricular mass by body surface area.7
Left ventricular hypertrophy (LVH) was defined
as LVMI >139 g/m2 in men and >109
g/m2 in women. Pulsed Doppler
recordings were made from the standard apical 4-chamber view.
Mitral inflow velocity was recorded with the sample volume at the
mitral anulus level; the average of 
3 cardiac cycles was taken. The
following measurements were made: peak velocity of early left
ventricular filling (E), peak velocity of late
ventricular filling (A), and the ratio between early and
late flow velocity peaks (E/A). The E/A ratio was then normalized by
dividing it by the heart rate (E/Ac). An E/Ac of <1 was considered the
cutoff point for identifying patients with diastolic
dysfunction.
Ambulatory Blood Pressure Monitoring
Ambulatory blood pressure (ABP) was monitored with a fully
automatic portable recorder (SpaceLabs 90209) equipped with an
occlusion cuff to determine systolic blood pressure (SBP) and
diastolic blood pressure (DBP) every 15 minutes during
daytime (6 AM to 10 PM) and every 30 minutes
during nighttime (10 PM to 6 AM). The cuffs
were positioned on the nondominant arm. The patients were instructed to
perform their usual activities. Mean 24-hour SBP and DBP were
calculated.
Baroreflex Sensitivity Assessment
The evaluations were made in the morning in a quiet and
light-attenuated room, with an ambient temperature of 
24°C. Before
evaluation, the patients lay supine for 30 minutes to allow their
cardiovascular mechanisms to reach steady state.
Cardiac baroreceptor sensitivity was assessed by means of power
spectral analysis8 with the patients in a supine
position during spontaneous and metronome-paced breathing at 0.27 Hz
and after a head-up tilt test at 70° for 5 minutes. During each
session, the signals of the R-R interval (model 78354C, Hewlett
Packard), respiration (by means of the impedance pneumograph; model
78354C, Hewlett Packard), and noninvasive blood pressure (Finapres
model 2300, Ohmeda) were continuously and simultaneously
recorded as previously described.8
Univariate and bivariate9 spectral
analyses of time series were made with the autoregressive
approach.8 The spectral baroreflex gain is calculated as
the square root of the ratio between the R-R interval and SBP spectral
components in either the high-frequency or the low-frequency band, when
the coherence between these components is >0.5.10
However, we considered this index in the high-frequency band (from 0.15
to 0.40 Hz; -HF, ms/mm Hg) because of the high percentage of
coherence >0.5.8
Statistical Analysis
The data are expressed as mean±SD values. Linear
univariate correlations were analyzed by means of
Pearson's product moment; the multivariate
correlations were analyzed by means of multiple correlation.
The between-group differences in -HF were evaluated by means of
multifactorial ANOVA for repeated measures, with age used as a
covariate. A value of P<0.05 was considered statistically
significant.
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Results |
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Analysis of Overall Population of Hypertensive Patients
The clinical characteristics of the studied population are shown in Table 1. Nineteen (31%) of the patients had diastolic dysfunction, and 16 (26%) had LVH (including 6 with diastolic dysfunction). ABP monitoring resulted in mean 24-hour SBP and DBP of 142±13 and 88±15 mm Hg, respectively. In regard to spectral baroreflex gain, the
-HF values
in the hypertensive patients as a whole were significantly less than
those in the control subjects during spontaneous respiration (11.4±7
versus 17.3±8 ms/mm Hg) and during controlled breathing (7.4±5
versus 10.6±5 ms/mm Hg) and tilt (4.8±3 versus 8±3 ms/mm Hg).
Univariate analysis showed that the presence of
diastolic ventricular dysfunction significantly
correlated with age (r=-0.65, P<0.0001),
LVMI (r=-0.34, P=0.01), and -HF during
controlled breathing (r=0.31, P=0.014) (Figure 1) but did not correlate with the values
of ABP. LVMI significantly correlated with age (r=0.31,
P=0.02), mean 24-hour SBP (r=0.28,
P=0.039), and -HF during controlled breathing
(r=-0.32, P=0.02). At
multivariate analysis, age was the only
independent variable (r=-0.63,
P<0.001).
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Patients With and Without Left Ventricular
Diastolic Dysfunction
The clinical characteristics of the hypertensive patients with and
without diastolic dysfunction are given in Table 1.
When considered separately with age as covariate, the subgroups had a
similar mean R-R interval (Table 2). In
contrast, the -HF values were lower in the patients with
diastolic dysfunction than in normal subjects and
hypertensive patients without diastolic dysfunction during
spontaneous respiration (P<0.05) and controlled breathing
(P<0.05); during tilt, the patients with and without
diastolic dysfunction had similar -HF values (Table 2 and Figure 2A). The -HF
values of the control subjects were always significantly higher than
those of the hypertensive patients with and without
diastolic dysfunction.
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) and without (
)
diastolic dysfunction and in controls (
) during
spontaneous respiration (SR), controlled respiration (CR), and tilt. B,
Trends of 
)
and without (
) LVH and in controls (
P<0.01.
Patients With and Without LVH
The clinical characteristics of the hypertensive patients with and
without LVH are given in Table 3. The 2
subgroups had similar mean R-R and -HF values (Table 2 and
Figure 2B). The -HF values of the control subjects were
always significantly higher than those of the hypertensive patients
with LVH; in the patients without LVH, -HF was significantly lower
than in control subjects at baseline and was nonsignificantly lower
during controlled breathing and tilt.
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Changes in -HF During Controlled Breathing and Tilt
The values of -HF decreased during controlled breathing and
tilt in all 3 groups; however, the reduction in the hypertensive
patients with diastolic dysfunction was much less than that
in the patients without dysfunction and in normal subjects (Figure 2A). Moreover, the tilt values of patients with and without
diastolic dysfunction, which were statistically different
at baseline and during controlled breathing, became almost similar
(Figure 2A). When this change was evaluated in hypertensive
patients with and without LVH, it was found to be similar in the 2
groups (Figure 2B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The main result of the present study is the finding that older age and less baroreflex heart rate response characterize the patients with previously unknown and untreated systemic hypertension and left ventricular diastolic dysfunction (who represented 31% of the 61 consecutive patients in our study population).
The role of each of the parameters considered in this study as a possible determinant of left ventricular diastolic dysfunction is separately discussed below.
Age
Although -HF and LVMI were also associated with
diastolic dysfunction at univariate
analysis, multivariate analysis showed
that age was the only independent parameter predictive of
the occurrence of diastolic impairment. The importance of
age found in our study is in agreement with previously published
data.2 11
Systolic Blood Pressure
Pressure load did not seem to be a determinant of left
ventricular diastolic dysfunction because, when
evaluated by means of ABP, it did not correlate with
diastolic impairment at either univariate or
multivariate analysis. This finding is in
contrast with previously published results12 13 showing a
significant correlation between ABP indices and diastolic
dysfunction; however, these studies analyzed normal subjects
and hypertensive patients as a continuum, and this may have given rise
to a spurious correlation since hypertensive patients can be expected
to have lower values of E/Ac and higher values of ABP than normal
subjects. On the other hand, pressure load was associated with the
occurrence of LVH. LVMI also correlated with the presence of
diastolic dysfunction, a finding that is in contrast with
those of previous studies showing no correlation between the 2
parameters.14 However, the same authors
stressed the fact that the major limit of cross-sectional studies is
that patients with abnormal left ventricular filling may
have an increased LVMI even if it remains within the normal range.
Baroreflex Sensitivity
-HF has been widely demonstrated to be a reliable measure of
baroreflex sensitivity.10 15 Although
multivariate analysis did not identify it as an
independent parameter in predicting the occurrence of left
ventricular diastolic dysfunction, it was
significantly different in our hypertensive patients with and without
diastolic dysfunction. The absence of any significant role
at multivariate analysis may be due to the fact
that the weight of age in the analysis is so strong that it
cancels that of other factors. Moreover, age is itself capable of
modifying reflex cardiac activity, since it has been shown that
baroreflex sensitivity tends to decrease with aging.16
Furthermore, from a mathematical point of view, it is also possible
that the small changes in the values of E/Ac at different ages
(although hardly significant in clinical terms) may play a greater role
than the greater changes in baroreflex sensitivity. We therefore
decided to dichotomize our population into patients with and without
diastolic dysfunction using age as covariate and found that
there was a difference in their -HF values. This may have been due
to our selected population (patients with previously unknown and
untreated essential hypertension), which allowed us to evaluate the
role of autonomic nervous system activity in a very early disease
phase. An impaired sympathovagal balance during the early phases of
hypertension has been revealed by various methods17 18 ;
however, these generally placed greater emphasis on increased
sympathetic tone, and only a few evaluated the presence of impaired
tonic19 and reflex20 vagal activity.
Our study suggests that hypertensive patients show an impaired
baroreflex heart rate response and that this is particularly evident in
those with functional and anatomic involvement. Greater impairment in
the reflex control of circulation is also suggested by another
interesting finding of this study: the different trend of -HF
changes in the 3 groups. It is worth noting that patients without
dysfunction still have a partial reflex control of circulation, which
is completely lost in those with diastolic dysfunction;
when a reduction in -HF occurs during tilt, the patients with
dysfunction are not capable of further reducing their baroreflex
sensitivity.
The cross-sectional nature of the present study does not allow us to explore further the reason for this correlation or to identify a causal link between the cardiac abnormality and autonomic nervous system activity imbalance. It may be that the 2 abnormalities are coincidental, but different mechanisms are possible. A reduced baroreflex heart rate response and depressed E/Ac ratio may coexist only at a more advanced disease stage; however, our patients with diastolic dysfunction did not have significantly higher blood pressure values than the other hypertensive patients (Table 2). Impaired diastolic filling may increase the firing of the cardiopulmonary receptors that have a tonic inhibitory effect on arterial baroreflex responsiveness through the sympathetic afference21 ; this reduced restraint from the heart might occur at the same time as an increased positive feedback mechanism. In addition, a reduction in the inhibitory effects on sympathetic drive exerted by cardiopulmonary receptors with vagal afferent, as well as resetting of arterial baroreceptors, might also favor the progression of sympathetic activation characterizing the early hypertensive state. Finally, the possibilities described are not mutually exclusive.
Limitation of the Study
Although it only measures diastolic
ventricular filling, we used E/Ac as an indirect measure of
diastolic dysfunction since it is a generally accepted
method; other methods of analyzing diastolic dysfunction,
such as radioisotopic or contrastographic ventriculography, are more
accurate but also more difficult to obtain.
Conclusions
Diastolic dysfunction is related to age and abnormal
baroreflex sensitivity; ABP does not influence diastolic
dysfunction. Further prospective studies are needed to assess the
causal nature of the relationship between baroreflex bradycardia
abnormalities and functional and structural abnormalities in
hypertensive patients.
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Acknowledgments |
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This study was made possible thanks to the cooperation of the Associazione per la Ricerca in Cardiologia, Bari. The authors wish to thank Dr Nicola Di Venere and Dr Antonella Mannarini for analyzing the echocardiograms, Giovanna Pontrandolfo for technical support, and Giuseppe Salente for secretarial assistance.
Received October 19, 1998; first decision November 5, 1998; accepted January 12, 1999.
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